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Chronic Pancreatitis☆
Chronic Pancreatitis☆ TE Adrian, United Arab Emirates University, Al Ain, UAE ã 2014 Elsevier Inc. All rights reserved.
Introduction Definition Classification Consequences Associated Disorders Etiology Epidemiology Pathophysiology Signs and Symptoms Standard Therapies Experimental Therapies Animal Models Journal Citations
1 1 1 1 2 2 2 2 3 3 4 4 4
Introduction Chronic pancreatitis is characterized by a slowly progressing destruction of the pancreatic acini, with varying amounts of inflammation, fibrosis, and dilatation and distortion of the pancreatic ducts (Lankisch, 2001). With chronic relapsing pancreatitis, acute attacks are superimposed on a background of chronic disease. Varying degrees of pancreatic destruction with exocrine and/or endocrine insufficiency can occur. Chronic pancreatitis is associated with moderate to intractable upper abdominal pain that is usually related to food intake (Bornman et al., 2003). The pain may also be located primarily in the back or radiate through to the back as in acute pancreatitis. Since the pain can persist for several years before other manifestations become apparent, narcotic dependence is a frequent complication of this condition. Treatment of the pain includes the use of analgesics and administration of large amounts of pancreatic enzyme supplements. Surgical therapy includes drainage of an obstruction or of an associated pseudocyst. Intractable pain may also require partial or even total pancreatectomy. Some who have undergone total pancreatectomy for severe pain have had successful transplantation of their own islets to prevent diabetes (Panaro et al., 2003; Watkins et al., 2003).
Definition Chronic pancreatitis is a chronic inflammatory disorder associated with irregular intra- and perilobular fibrosis and destruction and loss of exocrine parenchyma, usually accompanied by severe pain. Chronic pancreatitis ultimately leads to pancreatic exocrine failure (pancreatic insufficiency) with or without diabetes mellitus.
Classification Pancreatitis has been classified as acute or chronic on the basis of morphologic criteria and relapse. The latter classification recognized that a single episode of acute pancreatitis may have implications for pancreatic morphology and function, and that a patient with silent underlying disease may present for the first time with an acute attack, but may in fact have chronic disease. It is not unusual for a patient to present with chronic pain and abnormal pancreatic function tests although the findings of endoscopic retrograde cholangiopancreatography (ERCP) are normal. The reverse can also be true. The Marseilles-Rome classification of 1988 states that the morphological changes associated with acute pancreatitis are, as a rule, reversible. However, if the necrosis involves a segment of the main pancreatic duct, stenosis may result and lead to duct obstruction and chronic pancreatitis caudal to the stenosis.
☆
Change History: August 2014. TE Adrian has been updated the abstract, text and reference.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.04921-7
1
2
Chronic Pancreatitis
Consequences The major consequences of chronic pancreatitis are severe chronic pain, pancreatic insufficiency, and diabetes (Lankisch, 2001). Alcoholic pancreatitis is associated with neural changes including neural proliferation, damage to the perineurium, an increase in the production of sensory transmitters, and an interaction between inflammatory cells and the altered innervation (Bornman et al., 2003). All of these changes are implicated in the development of the severe pain associated with this condition. Pancreatic insufficiency results from destruction of the exocrine tissue, as well as from ductal obstruction. The destruction of the exocrine parenchyma is associated with calcification. Development of pseudocysts is another consequence of both acute and chronic pancreatitis.
Associated Disorders Chronic pancreatitis usually results from multiple attacks of acute pancreatitis. Given the location of the pancreas and its adjacent structures, progressive inflammatory disease may result in encasement of the common bile duct with fibrosis leading to obstructive jaundice. Gastrointestinal bleeding may result from splenic vein thrombosis with formation of gastric varices and subsequent hemorrhage or a pseudoaneurysm of a large artery in the peripancreatic area. Abdominal pain and an associated mass may be present with a pseudocyst (Sahel and Barthet, 1996). Malabsorption and endocrine insufficiency results when there is marked destruction of the exocrine parenchyma. Diabetes mellitus is another feature of advanced disease and occurs in about one third of patients. These patients may require insulin therapy, but this diabetes is not usually associated with ketoacidosis. Chronic pancreatitis patients have an increased risk of developing pancreatic adenocarcinoma. The risk is difficult to assess because pancreatic cancers themselves induce a chronic inflammation in the surrounding pancreas, making it impossible to determine which condition caused the other. Recent studies on familial chronic pancreatitis suggest that the risk of developing cancer is markedly increased in patients who are also smokers.
Etiology The dominant etiological factor in the development of chronic pancreatitis in the Western world is ethanol abuse, which accounts for approximately 80% of patients. Etiological factors other than alcohol that may contribute to chronic pancreatitis include hypercalcemia, hyperlipidemia, and hereditary (Lowenfels and Maisonneuve, 2002). A common, alcohol-independent form of pancreatitis occurs in southern India and other tropical areas. While the precise etiology of tropical pancreatitis remains unknown, numerous nutritional and environmental factors, such as protein and calorie malnutrition, are implicated (Lowenfels and Maisonneuve, 2002). Smoking appears to be a risk factor for chronic pancreatitis independent of alcohol.
Epidemiology Chronic pancreatitis is a condition that is typically associated with heavy drinking. Chronic pancreatitis can also be associated with heredity in conditions such as cystic fibrosis, as well as being idiopathic (Lowenfels and Maisonneuve, 2002). Precise information on the prevalence of chronic pancreatitis is difficult to obtain because of confusion in defining acute pancreatitis, acute relapsing pancreatitis, and chronic pancreatitis. The incidence from hospital discharge records in the United States is 6.7 per 100,000 males and 3.2 per 100,000 females. In general, chronic pancreatitis is a relatively uncommon condition and occurs less frequently than cirrhosis as a consequence of alcohol abuse. African Americans, both men and women, are three times more prone to develop chronic pancreatitis than Caucasians, with the reverse being true for cirrhosis (Lowenfels and Maisonneuve, 2002).
Pathophysiology Inflammation can spread easily since the pancreas is located in the retroperitoneal space with no capsule. Recurrent episodes of pancreatic necrosis resulting from attacks of acute pancreatitis appear to lead to fibrosis. On the other hand, some patients develop chronic pancreatitis without bouts of severe acute disease. There is a poor correlation between the number and severity of acute pancreatitis attacks and subsequent development of the chronic condition (Lankisch, 2001). Ethanol can affect the integrity of the pancreas in several ways. It has effects on blood flow that predispose towards ischemia and may be directly toxic to acinar cells or have metabolic effects that enhance acinar cell injury (Brock et al., 2013; Petersen and Forsmark, 2002). Moreover, alcohol can increase pressure of the sphincter of Oddi to such an extent that there is a reflux of bile into the pancreatic duct (Petersen and Forsmark, 2002). Furthermore, the enhanced ductal pressure leads to an increase in ductal
Chronic Pancreatitis
3
permeability permitting the movement of ductal contents into the interstitial space (Brock et al., 2013; Petersen and Forsmark, 2002). Specific gene mutations are responsible for the development of pancreatitis include those in trypsinogen and pancreatic secretory trypsin inhibitor. The fibrosis that occurs in chronic pancreatitis and pancreatic cancer is a function of the stellate cells which, when activated, produce large amounts of collagen (Apte and Wilson, 2002). This activation involves a complex interplay of growth factors and cytokines, particularly transforming growth factor beta (TGFb) (Brock et al., 2013).
Signs and Symptoms Chronic pancreatitis is typically accompanied by moderate to intractable abdominal pain radiating through to the back. However, the pain may be mild or even absent in some patients, or episodic in chronic relapsing pancreatitis. The pain may persist for years before other manifestations, such as calcification, diabetes, and malabsorption, appear (Bornman et al., 2003). Rarely, these other signs may be the initial manifestations in the absence of abdominal pain. Malabsorption results in steatorrhea from the fat entering the colon with additional osmotic diarrhea resulting from the presence of other nutrients in the colon. Weight loss may result from anorexia or malabsorption (Petersen and Forsmark, 2002).
Standard Therapies Treatment of chronic pancreatitis is directed toward preventing further pancreatic injury, relieving pain, and replacing lost endocrine/exocrine function. Prevention of further pancreatic injury may be prevented by abstaining from alcohol. Moreover, the avoidance of alcohol may prevent further exacerbations of abdominal pain and further episodes of acute pancreatitis. However, acute alcoholic pancreatitis can result in chronic pancreatitis, even with abstinence from alcohol. The replacement of lost exocrine function is described under the record ‘Pancreatic insufficiency’ and the treatment of the endocrine dysfunction is considered under the record ‘Diabetes Mellitus’. Treatment of the abdominal pain associated with chronic pancreatitis is a difficult challenge. It should begin with non-addictive analgesics before attempting narcotics (Andren-Sandberg et al., 2002; Karl et al., 2002). Pain may be reduced by suppressing the remaining endogenous pancreatic acinar function with large doses of supplemental pancreatic enzymes. However, non-enteric coated capsules were required (Singh and Toskes, 2003; Trifan et al., 2001). This approach is most successful for those with idiopathic pancreatitis as compared to those with alcoholic pancreatitis and patients who respond best to enzyme therapy are those with mild-to-moderate exocrine insufficiency and minimal changes on endoscopic retrograde cholangiopancreatography (ERCP). Any complication that may be responsible for pain, such as pseudocysts or compression of adjacent visceral structures, needs to be excluded or dealt with prior to administration of analgesics (Andren-Sandberg et al., 2002; Karl et al., 2002). Analgesic therapy should begin with non-narcotic agents, such as acetaminophen or nonsteroidal antiinflammatory agents. However, opioids are often required to control pain. The type and dose of analgesic varies between patients, with treatment adapted to individual needs using the lowest dose necessary to control pain (Andren-Sandberg et al., 2002; Karl et al., 2002).
Agent Name Acetaminophen Nonsteroidal antiinflammatory drugs Pentazocine Tramadol Buprenorphine
Morphine Proton pump inhibitors
Discussion Acetaminophen is an analgesic for the treatment of moderate pain in chronic pancreatitis. It can be combined with nonsteroidal antiinflammatory agents (Andren-Sandberg et al., 2002). Like acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors, can be used to control modest pain. The nonsteroidal antiinflammatory agents are most likely to be of benefit early in the course of the disease when the pain is secondary to invasion of the exocrine parenchyma by inflammatory cells (Toskes, 2002). Pentazocine is an opioid kappa receptor agonist with weak mu receptor partial agonistic properties. It is used as an analgesic when non-opioid analgesics fail to relieve the pain (Andren-Sandberg et al., 2002). Tramadol is a weak mu opioid receptor agonist and an inhibitor of norepinephrine and serotonin reuptake in brain. It is useful for treating pain when pentazocine and nonsteroidal antiinflammatory agents are ineffective (Karl et al., 2002). Buprenorphine is a potent, long-acting phenanthrene derivative that is a partial mu opioid receptor agonist. It is useful for the treatment of severe pain when other drugs are ineffective. Buprenorphine (0.3 mg) is very effective when given by epidural injection to control pain in chronic pancreatitis (Karl et al., 2002). There may be pain relief for up to six months following epidural buprenorphine. Morphine is a nonselective opioid agonist used to control pain when other analgesics are ineffective (Karl et al., 2002). A proton pump inhibitor, such as omeprazole, lansoprazole, or esomeprazole, should be co-administered with the nonsteroidal antiinflammatory agents since secretion of pancreatic bicarbonate to neutralize gastric acid is impaired in these patients and, therefore, duodenal mucosal integrity is already compromised (Toskes, 2002). Patients also receive proton pump inhibitors to increase the effective delivery of pancreatic enzyme supplements, unless they are enteric coated.
Note: Treatment of malabsorption with pancreatic enzyme supplements is addressed in the record ‘Pancreatic Insufficiency’.
4
Chronic Pancreatitis
Experimental Therapies New therapies for the treatment of chronic pancreatitis are targeted at suppressing stimulation of the exocrine pancreas or at peripheral opioid receptors to prevent narcotic addiction.
Agent Name Octreotide
Loxiglumide ADL 01-0101 CP-96345 and CRRP 8-37
Discussion Octreotide, a long-acting somatostatin analog, has been found to be effective in reducing pain associated with severe, chronic pancreatitis Uhl et al. (1999). Like pancreatic enzyme supplements, octreotide suppresses circulating levels of cholecystokinin and directly inhibits pancreatic secretory function. Octreotide also exhibits some antinociceptive activity (Brunaud et al., 2001). Octreotide has also been used successfully in closure of external pancreatic fistulas and in the treatment of pseudocysts (Bosman-Vermeeren et al., 1996). Loxiglumide, a cholecystokinin receptor antagonist, has displayed modest but significant effectiveness in the treatment of abdominal and back pain associated with chronic pancreatitis (Shiratori et al., 2002). ADL 01–0101, a peripherally active kappa opioid receptor agonist, is reported to be effective in reducing pain associated with chronic pancreatitis in those failing to respond to mu opioid receptor agonists (Eisenach et al., 2003). Substance P and calcitonin gene related peptide (CGRP) are sensory peptide neurotransmitters released from primary sensory fibers. CP-96345 is an antagonist of the neurokinin 1 receptor to which substance P binds. CGRP 8–37 is a truncated CGRP analog that acts as a CGRP antagonist. Intrathecal infusion of CP-96345 and CGRP 8–37 significantly attenuated behavioral pain responses in a rat model of chronic pancreatitis (Liu et al., 2011).
Animal Models Trinitrobenzene sufonic acid (TNBS)-induced pancreatic fibrosis is used to create a rat model of chronic pancreatitis. The fibrosis, which follows necroinflammation, is induced by infusion of this chemical toxin into the pancreatic duct Apte and Wilson (2002). The pattern of fibrosis closely resembles that of chronic pancreatitis in humans. Dibutyltin chloride (DBTC)-induced pancreatic fibrosis involves the administration of a single intravenous dose of this substance to rats. Severe pancreatitis develops within one week and is followed by marked fibrosis within four weeks Apte and Wilson (2002). The DBTC method has been modified by addition of 10% ethanol to the drinking water, producing a chronic model for studying visceral pain (Vera-Portocarrero et al., 2003).
Journal Citations Andren-Sandberg A, Hoem D, and Gislason H (2002) Pain management in chronic pancreatitis. European Journal Of Gastroenterology & Hepatology 14(9): 957–970. Bornman PC, Marks IN, Girdwood AW, Berberat PO, Gulbinas A, and Bu¨chler MW (2003) Pathogenesis of pain in chronic pancreatitis: Ongoing enigma. World Journal of Surgery 27 (11): 1175–1182. Bosman-Vermeeren JM, Veereman-Wauters G, Broos P, and Eggermont E (1996) Somatostatin in the treatment of a pancreatic pseudocyst in a child. Journal Of Pediatric Gastroenterology And Nutrition 23(4): 422–425. Brock C, Nielsen LM, Lelic D, and Drewes AM (2013) Pathophysiology of chronic pancreatitis. World Journal of Gastroenterology 19(42): 7231–7240. Brunaud L, Sebbag H, Marchal F, Verdier A, Bresler L, Tortuyaux JM, and Boissel P (2001) Evaluation of somatostatin or octreotide efficacy in the treatment of external pancreatic fistulas. Annales de Chirurgie 126(1): 34–41. Eisenach JC, Carpenter R, and Curry R (2003) Analgesia from a peripherally active k-opioid agonist in patients with chronic pancreatitis. Pain 101: 89–95. Lankisch PG (2001) Natural course of chronic pancreatitis. Pancreatology 1(1): 3–14. Liu L, Shenoy M, and Pasricha PJ (2011) Substance P and calcitonin gene related peptide mediate pain in chronic pancreatitis and their expression is driven by nerve growth factor. JOP: Journal Of The Pancreas. [Electronic Resource] 12(4): 389–394. Panaro F, Testa G, Bogetti D, Sankary H, Helton WS, and Benedetti E (2003) Auto-islet transplantation after pancreatectomy. Expert Opinion On Biological Therapy 3(2): 207–214. Petersen JM and Forsmark CE (2002) Chronic pancreatitis and maldigestion. Seminars in Gastrointestinal Disease 13(4): 191–199. Sahel J and Barthet M (1996) Medical and endoscopic treatment of chronic pancreatitis. La Revue du praticien 46(6): 715–721. Shiratori K, Takeuchi T, Satake K, and Matsuno S (2002) Study Group of Loxiglumide in Japan. Clinical evaluation of oral administration of a cholecystokinin-A receptor antagonist (loxiglumide) to patients with acute, painful attacks of chronic pancreatitis: A multicenter dose–response study in Japan. Pancreas 25(1): E1–E5. Singh VV and Toskes PP (2003) Medical therapy for chronic pancreatitis pain. Current Gastroenterology Reports 5(2): 110–116. Trifan A, Balan G, and Stanciu C (2001) Pancreatic enzymes replacement therapy in chronic pancreatitis: An update. Revista medico-chirurgicala˘ a Societa˘¸tii de Medici s¸i Naturalis¸ti din Ias¸i 105(4): 646–650. Uhl W, Anghelacopoulas SE, Friess H, and Bu¨chler MW (1999) The role of octreotide and somatostatin in acute and chronic pancreatitis. Digestion 60(Suppl. 2): S23–S31. Vera-Portocarrero LP, Lu Y, and Westlund KN (2003) Nociception in persistent pancreatitis in rats: Effects of morphine and neuropeptide alterations. Anesthesiology 98: 474–484. Watkins JG, Krebs A, and Rossi RL (2003) Pancreatic autotransplantation in chronic pancreatitis. World Journal of Surgery 27(11): 1235–1240. Book Citations Apte MV and Wilson JS (2002) Experimental models of pancreatic fibrogenesis and the role of stellate cells. In: Bu¨chler MW, Friess H, Uhl W, and Malfertheiner P (eds.) Chronic Pancreatitis: Novel Concepts in Biology and Therapy, pp. 113–133. UK: Blackwell Science Oxford. Karl S, Glasbrenner B, Schulz HU, and Malfertheiner P (2002) An integrated approach to the non-operative treatment of pain in chronic pancreatitis. In: Bu¨chler MW, Friess H, Uhl W, and Malfertheiner P (eds.) Chronic Pancreatitis: Novel Concepts in Biology and Therapy, pp. 409–419. UK: Blackwell Science Oxford. Lowenfels AB and Maisonneuve P (2002) Epidemiology of chronic pancreatitis and the risk of cancer. In: Bu¨chler MW, Friess H, Uhl W, and Malfertheiner P (eds.) Chronic Pancreatitis: Novel Concepts in Biology and Therapy, pp. 29–36. UK: Blackwell Science Oxford.
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Toskes PP (2002) Treatment of pain in chronic pancreatitis: Inhibition of enzyme secretion. In: Bu¨chler MW, Friess H, Uhl W, and Malfertheiner P (eds.) Chronic Pancreatitis: Novel Concepts in Biology and Therapy, pp. 389–394. UK: Blackwell Science Oxford.
Further Reading MW Bu¨chler, H Friess, W Uhl and P Malfertheiner (Eds.), Chronic pancreatitis. Blackwell, Oxford, UK. 2002.
Relevant – Web Sites This NIH site provides a brief summary of the symptoms, diagnosis, and treatment of pancreatitis: http://www.niddk.nih.gov/health/digest/pubs/pancreas/pancreas.htm. This site, authored by Paul Yakshe, provides comprehensive coverage of the pathophysiology, epidemiology, presenting history, physical findings, laboratory and imaging studies associated with pancreatitis, along with discussions of medical and surgical treatments, and recommended diets: http://www.emedicine.com/med/topic1721.htm. This National Library of Medicine site provides a synopsis of the epidemiology, symptoms, signs and tests, treatments, prognosis, complications associated with chronic pancreatitis: http://www.nlm.nih.gov/medlineplus/ency/article/000221.htm. This site, sponsored by Merck, provides information on the etiology, pathogenesis, symptoms and signs, diagnosis, and treatment of chronic pancreatitis: http://www.merck.com/ mrkshared/mmanual/section3/chapter26/26c.jsp.
Introduction Definition Classification Consequences Associated Disorders Etiology Epidemiology Pathophysiology Signs and Symptoms Standard Therapies Experimental Therapies Animal Models Journal Citations
1 1 1 1 2 2 2 2 3 3 4 4 4
Introduction Chronic pancreatitis is characterized by a slowly progressing destruction of the pancreatic acini, with varying amounts of inflammation, fibrosis, and dilatation and distortion of the pancreatic ducts (Lankisch, 2001). With chronic relapsing pancreatitis, acute attacks are superimposed on a background of chronic disease. Varying degrees of pancreatic destruction with exocrine and/or endocrine insufficiency can occur. Chronic pancreatitis is associated with moderate to intractable upper abdominal pain that is usually related to food intake (Bornman et al., 2003). The pain may also be located primarily in the back or radiate through to the back as in acute pancreatitis. Since the pain can persist for several years before other manifestations become apparent, narcotic dependence is a frequent complication of this condition. Treatment of the pain includes the use of analgesics and administration of large amounts of pancreatic enzyme supplements. Surgical therapy includes drainage of an obstruction or of an associated pseudocyst. Intractable pain may also require partial or even total pancreatectomy. Some who have undergone total pancreatectomy for severe pain have had successful transplantation of their own islets to prevent diabetes (Panaro et al., 2003; Watkins et al., 2003).
Definition Chronic pancreatitis is a chronic inflammatory disorder associated with irregular intra- and perilobular fibrosis and destruction and loss of exocrine parenchyma, usually accompanied by severe pain. Chronic pancreatitis ultimately leads to pancreatic exocrine failure (pancreatic insufficiency) with or without diabetes mellitus.
Classification Pancreatitis has been classified as acute or chronic on the basis of morphologic criteria and relapse. The latter classification recognized that a single episode of acute pancreatitis may have implications for pancreatic morphology and function, and that a patient with silent underlying disease may present for the first time with an acute attack, but may in fact have chronic disease. It is not unusual for a patient to present with chronic pain and abnormal pancreatic function tests although the findings of endoscopic retrograde cholangiopancreatography (ERCP) are normal. The reverse can also be true. The Marseilles-Rome classification of 1988 states that the morphological changes associated with acute pancreatitis are, as a rule, reversible. However, if the necrosis involves a segment of the main pancreatic duct, stenosis may result and lead to duct obstruction and chronic pancreatitis caudal to the stenosis.
☆
Change History: August 2014. TE Adrian has been updated the abstract, text and reference.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.04921-7
1
2
Chronic Pancreatitis
Consequences The major consequences of chronic pancreatitis are severe chronic pain, pancreatic insufficiency, and diabetes (Lankisch, 2001). Alcoholic pancreatitis is associated with neural changes including neural proliferation, damage to the perineurium, an increase in the production of sensory transmitters, and an interaction between inflammatory cells and the altered innervation (Bornman et al., 2003). All of these changes are implicated in the development of the severe pain associated with this condition. Pancreatic insufficiency results from destruction of the exocrine tissue, as well as from ductal obstruction. The destruction of the exocrine parenchyma is associated with calcification. Development of pseudocysts is another consequence of both acute and chronic pancreatitis.
Associated Disorders Chronic pancreatitis usually results from multiple attacks of acute pancreatitis. Given the location of the pancreas and its adjacent structures, progressive inflammatory disease may result in encasement of the common bile duct with fibrosis leading to obstructive jaundice. Gastrointestinal bleeding may result from splenic vein thrombosis with formation of gastric varices and subsequent hemorrhage or a pseudoaneurysm of a large artery in the peripancreatic area. Abdominal pain and an associated mass may be present with a pseudocyst (Sahel and Barthet, 1996). Malabsorption and endocrine insufficiency results when there is marked destruction of the exocrine parenchyma. Diabetes mellitus is another feature of advanced disease and occurs in about one third of patients. These patients may require insulin therapy, but this diabetes is not usually associated with ketoacidosis. Chronic pancreatitis patients have an increased risk of developing pancreatic adenocarcinoma. The risk is difficult to assess because pancreatic cancers themselves induce a chronic inflammation in the surrounding pancreas, making it impossible to determine which condition caused the other. Recent studies on familial chronic pancreatitis suggest that the risk of developing cancer is markedly increased in patients who are also smokers.
Etiology The dominant etiological factor in the development of chronic pancreatitis in the Western world is ethanol abuse, which accounts for approximately 80% of patients. Etiological factors other than alcohol that may contribute to chronic pancreatitis include hypercalcemia, hyperlipidemia, and hereditary (Lowenfels and Maisonneuve, 2002). A common, alcohol-independent form of pancreatitis occurs in southern India and other tropical areas. While the precise etiology of tropical pancreatitis remains unknown, numerous nutritional and environmental factors, such as protein and calorie malnutrition, are implicated (Lowenfels and Maisonneuve, 2002). Smoking appears to be a risk factor for chronic pancreatitis independent of alcohol.
Epidemiology Chronic pancreatitis is a condition that is typically associated with heavy drinking. Chronic pancreatitis can also be associated with heredity in conditions such as cystic fibrosis, as well as being idiopathic (Lowenfels and Maisonneuve, 2002). Precise information on the prevalence of chronic pancreatitis is difficult to obtain because of confusion in defining acute pancreatitis, acute relapsing pancreatitis, and chronic pancreatitis. The incidence from hospital discharge records in the United States is 6.7 per 100,000 males and 3.2 per 100,000 females. In general, chronic pancreatitis is a relatively uncommon condition and occurs less frequently than cirrhosis as a consequence of alcohol abuse. African Americans, both men and women, are three times more prone to develop chronic pancreatitis than Caucasians, with the reverse being true for cirrhosis (Lowenfels and Maisonneuve, 2002).
Pathophysiology Inflammation can spread easily since the pancreas is located in the retroperitoneal space with no capsule. Recurrent episodes of pancreatic necrosis resulting from attacks of acute pancreatitis appear to lead to fibrosis. On the other hand, some patients develop chronic pancreatitis without bouts of severe acute disease. There is a poor correlation between the number and severity of acute pancreatitis attacks and subsequent development of the chronic condition (Lankisch, 2001). Ethanol can affect the integrity of the pancreas in several ways. It has effects on blood flow that predispose towards ischemia and may be directly toxic to acinar cells or have metabolic effects that enhance acinar cell injury (Brock et al., 2013; Petersen and Forsmark, 2002). Moreover, alcohol can increase pressure of the sphincter of Oddi to such an extent that there is a reflux of bile into the pancreatic duct (Petersen and Forsmark, 2002). Furthermore, the enhanced ductal pressure leads to an increase in ductal
Chronic Pancreatitis
3
permeability permitting the movement of ductal contents into the interstitial space (Brock et al., 2013; Petersen and Forsmark, 2002). Specific gene mutations are responsible for the development of pancreatitis include those in trypsinogen and pancreatic secretory trypsin inhibitor. The fibrosis that occurs in chronic pancreatitis and pancreatic cancer is a function of the stellate cells which, when activated, produce large amounts of collagen (Apte and Wilson, 2002). This activation involves a complex interplay of growth factors and cytokines, particularly transforming growth factor beta (TGFb) (Brock et al., 2013).
Signs and Symptoms Chronic pancreatitis is typically accompanied by moderate to intractable abdominal pain radiating through to the back. However, the pain may be mild or even absent in some patients, or episodic in chronic relapsing pancreatitis. The pain may persist for years before other manifestations, such as calcification, diabetes, and malabsorption, appear (Bornman et al., 2003). Rarely, these other signs may be the initial manifestations in the absence of abdominal pain. Malabsorption results in steatorrhea from the fat entering the colon with additional osmotic diarrhea resulting from the presence of other nutrients in the colon. Weight loss may result from anorexia or malabsorption (Petersen and Forsmark, 2002).
Standard Therapies Treatment of chronic pancreatitis is directed toward preventing further pancreatic injury, relieving pain, and replacing lost endocrine/exocrine function. Prevention of further pancreatic injury may be prevented by abstaining from alcohol. Moreover, the avoidance of alcohol may prevent further exacerbations of abdominal pain and further episodes of acute pancreatitis. However, acute alcoholic pancreatitis can result in chronic pancreatitis, even with abstinence from alcohol. The replacement of lost exocrine function is described under the record ‘Pancreatic insufficiency’ and the treatment of the endocrine dysfunction is considered under the record ‘Diabetes Mellitus’. Treatment of the abdominal pain associated with chronic pancreatitis is a difficult challenge. It should begin with non-addictive analgesics before attempting narcotics (Andren-Sandberg et al., 2002; Karl et al., 2002). Pain may be reduced by suppressing the remaining endogenous pancreatic acinar function with large doses of supplemental pancreatic enzymes. However, non-enteric coated capsules were required (Singh and Toskes, 2003; Trifan et al., 2001). This approach is most successful for those with idiopathic pancreatitis as compared to those with alcoholic pancreatitis and patients who respond best to enzyme therapy are those with mild-to-moderate exocrine insufficiency and minimal changes on endoscopic retrograde cholangiopancreatography (ERCP). Any complication that may be responsible for pain, such as pseudocysts or compression of adjacent visceral structures, needs to be excluded or dealt with prior to administration of analgesics (Andren-Sandberg et al., 2002; Karl et al., 2002). Analgesic therapy should begin with non-narcotic agents, such as acetaminophen or nonsteroidal antiinflammatory agents. However, opioids are often required to control pain. The type and dose of analgesic varies between patients, with treatment adapted to individual needs using the lowest dose necessary to control pain (Andren-Sandberg et al., 2002; Karl et al., 2002).
Agent Name Acetaminophen Nonsteroidal antiinflammatory drugs Pentazocine Tramadol Buprenorphine
Morphine Proton pump inhibitors
Discussion Acetaminophen is an analgesic for the treatment of moderate pain in chronic pancreatitis. It can be combined with nonsteroidal antiinflammatory agents (Andren-Sandberg et al., 2002). Like acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors, can be used to control modest pain. The nonsteroidal antiinflammatory agents are most likely to be of benefit early in the course of the disease when the pain is secondary to invasion of the exocrine parenchyma by inflammatory cells (Toskes, 2002). Pentazocine is an opioid kappa receptor agonist with weak mu receptor partial agonistic properties. It is used as an analgesic when non-opioid analgesics fail to relieve the pain (Andren-Sandberg et al., 2002). Tramadol is a weak mu opioid receptor agonist and an inhibitor of norepinephrine and serotonin reuptake in brain. It is useful for treating pain when pentazocine and nonsteroidal antiinflammatory agents are ineffective (Karl et al., 2002). Buprenorphine is a potent, long-acting phenanthrene derivative that is a partial mu opioid receptor agonist. It is useful for the treatment of severe pain when other drugs are ineffective. Buprenorphine (0.3 mg) is very effective when given by epidural injection to control pain in chronic pancreatitis (Karl et al., 2002). There may be pain relief for up to six months following epidural buprenorphine. Morphine is a nonselective opioid agonist used to control pain when other analgesics are ineffective (Karl et al., 2002). A proton pump inhibitor, such as omeprazole, lansoprazole, or esomeprazole, should be co-administered with the nonsteroidal antiinflammatory agents since secretion of pancreatic bicarbonate to neutralize gastric acid is impaired in these patients and, therefore, duodenal mucosal integrity is already compromised (Toskes, 2002). Patients also receive proton pump inhibitors to increase the effective delivery of pancreatic enzyme supplements, unless they are enteric coated.
Note: Treatment of malabsorption with pancreatic enzyme supplements is addressed in the record ‘Pancreatic Insufficiency’.
4
Chronic Pancreatitis
Experimental Therapies New therapies for the treatment of chronic pancreatitis are targeted at suppressing stimulation of the exocrine pancreas or at peripheral opioid receptors to prevent narcotic addiction.
Agent Name Octreotide
Loxiglumide ADL 01-0101 CP-96345 and CRRP 8-37
Discussion Octreotide, a long-acting somatostatin analog, has been found to be effective in reducing pain associated with severe, chronic pancreatitis Uhl et al. (1999). Like pancreatic enzyme supplements, octreotide suppresses circulating levels of cholecystokinin and directly inhibits pancreatic secretory function. Octreotide also exhibits some antinociceptive activity (Brunaud et al., 2001). Octreotide has also been used successfully in closure of external pancreatic fistulas and in the treatment of pseudocysts (Bosman-Vermeeren et al., 1996). Loxiglumide, a cholecystokinin receptor antagonist, has displayed modest but significant effectiveness in the treatment of abdominal and back pain associated with chronic pancreatitis (Shiratori et al., 2002). ADL 01–0101, a peripherally active kappa opioid receptor agonist, is reported to be effective in reducing pain associated with chronic pancreatitis in those failing to respond to mu opioid receptor agonists (Eisenach et al., 2003). Substance P and calcitonin gene related peptide (CGRP) are sensory peptide neurotransmitters released from primary sensory fibers. CP-96345 is an antagonist of the neurokinin 1 receptor to which substance P binds. CGRP 8–37 is a truncated CGRP analog that acts as a CGRP antagonist. Intrathecal infusion of CP-96345 and CGRP 8–37 significantly attenuated behavioral pain responses in a rat model of chronic pancreatitis (Liu et al., 2011).
Animal Models Trinitrobenzene sufonic acid (TNBS)-induced pancreatic fibrosis is used to create a rat model of chronic pancreatitis. The fibrosis, which follows necroinflammation, is induced by infusion of this chemical toxin into the pancreatic duct Apte and Wilson (2002). The pattern of fibrosis closely resembles that of chronic pancreatitis in humans. Dibutyltin chloride (DBTC)-induced pancreatic fibrosis involves the administration of a single intravenous dose of this substance to rats. Severe pancreatitis develops within one week and is followed by marked fibrosis within four weeks Apte and Wilson (2002). The DBTC method has been modified by addition of 10% ethanol to the drinking water, producing a chronic model for studying visceral pain (Vera-Portocarrero et al., 2003).
Journal Citations Andren-Sandberg A, Hoem D, and Gislason H (2002) Pain management in chronic pancreatitis. European Journal Of Gastroenterology & Hepatology 14(9): 957–970. Bornman PC, Marks IN, Girdwood AW, Berberat PO, Gulbinas A, and Bu¨chler MW (2003) Pathogenesis of pain in chronic pancreatitis: Ongoing enigma. World Journal of Surgery 27 (11): 1175–1182. Bosman-Vermeeren JM, Veereman-Wauters G, Broos P, and Eggermont E (1996) Somatostatin in the treatment of a pancreatic pseudocyst in a child. Journal Of Pediatric Gastroenterology And Nutrition 23(4): 422–425. Brock C, Nielsen LM, Lelic D, and Drewes AM (2013) Pathophysiology of chronic pancreatitis. World Journal of Gastroenterology 19(42): 7231–7240. Brunaud L, Sebbag H, Marchal F, Verdier A, Bresler L, Tortuyaux JM, and Boissel P (2001) Evaluation of somatostatin or octreotide efficacy in the treatment of external pancreatic fistulas. Annales de Chirurgie 126(1): 34–41. Eisenach JC, Carpenter R, and Curry R (2003) Analgesia from a peripherally active k-opioid agonist in patients with chronic pancreatitis. Pain 101: 89–95. Lankisch PG (2001) Natural course of chronic pancreatitis. Pancreatology 1(1): 3–14. Liu L, Shenoy M, and Pasricha PJ (2011) Substance P and calcitonin gene related peptide mediate pain in chronic pancreatitis and their expression is driven by nerve growth factor. JOP: Journal Of The Pancreas. [Electronic Resource] 12(4): 389–394. Panaro F, Testa G, Bogetti D, Sankary H, Helton WS, and Benedetti E (2003) Auto-islet transplantation after pancreatectomy. Expert Opinion On Biological Therapy 3(2): 207–214. Petersen JM and Forsmark CE (2002) Chronic pancreatitis and maldigestion. Seminars in Gastrointestinal Disease 13(4): 191–199. Sahel J and Barthet M (1996) Medical and endoscopic treatment of chronic pancreatitis. La Revue du praticien 46(6): 715–721. Shiratori K, Takeuchi T, Satake K, and Matsuno S (2002) Study Group of Loxiglumide in Japan. Clinical evaluation of oral administration of a cholecystokinin-A receptor antagonist (loxiglumide) to patients with acute, painful attacks of chronic pancreatitis: A multicenter dose–response study in Japan. Pancreas 25(1): E1–E5. Singh VV and Toskes PP (2003) Medical therapy for chronic pancreatitis pain. Current Gastroenterology Reports 5(2): 110–116. Trifan A, Balan G, and Stanciu C (2001) Pancreatic enzymes replacement therapy in chronic pancreatitis: An update. Revista medico-chirurgicala˘ a Societa˘¸tii de Medici s¸i Naturalis¸ti din Ias¸i 105(4): 646–650. Uhl W, Anghelacopoulas SE, Friess H, and Bu¨chler MW (1999) The role of octreotide and somatostatin in acute and chronic pancreatitis. Digestion 60(Suppl. 2): S23–S31. Vera-Portocarrero LP, Lu Y, and Westlund KN (2003) Nociception in persistent pancreatitis in rats: Effects of morphine and neuropeptide alterations. Anesthesiology 98: 474–484. Watkins JG, Krebs A, and Rossi RL (2003) Pancreatic autotransplantation in chronic pancreatitis. World Journal of Surgery 27(11): 1235–1240. Book Citations Apte MV and Wilson JS (2002) Experimental models of pancreatic fibrogenesis and the role of stellate cells. In: Bu¨chler MW, Friess H, Uhl W, and Malfertheiner P (eds.) Chronic Pancreatitis: Novel Concepts in Biology and Therapy, pp. 113–133. UK: Blackwell Science Oxford. Karl S, Glasbrenner B, Schulz HU, and Malfertheiner P (2002) An integrated approach to the non-operative treatment of pain in chronic pancreatitis. In: Bu¨chler MW, Friess H, Uhl W, and Malfertheiner P (eds.) Chronic Pancreatitis: Novel Concepts in Biology and Therapy, pp. 409–419. UK: Blackwell Science Oxford. Lowenfels AB and Maisonneuve P (2002) Epidemiology of chronic pancreatitis and the risk of cancer. In: Bu¨chler MW, Friess H, Uhl W, and Malfertheiner P (eds.) Chronic Pancreatitis: Novel Concepts in Biology and Therapy, pp. 29–36. UK: Blackwell Science Oxford.
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Toskes PP (2002) Treatment of pain in chronic pancreatitis: Inhibition of enzyme secretion. In: Bu¨chler MW, Friess H, Uhl W, and Malfertheiner P (eds.) Chronic Pancreatitis: Novel Concepts in Biology and Therapy, pp. 389–394. UK: Blackwell Science Oxford.
Further Reading MW Bu¨chler, H Friess, W Uhl and P Malfertheiner (Eds.), Chronic pancreatitis. Blackwell, Oxford, UK. 2002.
Relevant – Web Sites This NIH site provides a brief summary of the symptoms, diagnosis, and treatment of pancreatitis: http://www.niddk.nih.gov/health/digest/pubs/pancreas/pancreas.htm. This site, authored by Paul Yakshe, provides comprehensive coverage of the pathophysiology, epidemiology, presenting history, physical findings, laboratory and imaging studies associated with pancreatitis, along with discussions of medical and surgical treatments, and recommended diets: http://www.emedicine.com/med/topic1721.htm. This National Library of Medicine site provides a synopsis of the epidemiology, symptoms, signs and tests, treatments, prognosis, complications associated with chronic pancreatitis: http://www.nlm.nih.gov/medlineplus/ency/article/000221.htm. This site, sponsored by Merck, provides information on the etiology, pathogenesis, symptoms and signs, diagnosis, and treatment of chronic pancreatitis: http://www.merck.com/ mrkshared/mmanual/section3/chapter26/26c.jsp.