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Chronic Pancreatitis: Current Diagnosis and Treatment
Chronic Pancreatitis: Current Diagnosis and Treatment Sayeed Ikramuddin, MD and W. Scott Melvin, MD
Surgical Update
DEPARTMENT OF SURGERY, DIVISION OF GENERAL SURGERY, OHIO STATE UNIVERSITY, 410 W. 10TH AVENUE, COLUMBUS, OHIO
Abstract
Introduction
Chronic pancreatitis is a disease most commonly caused by alcoholism. It is a disease that manifests itself over the course of 10 to 20 years. It is associated with significant pain and narcotic addiction. Medical treatment appears to be limited, but the use of oral enzyme replacement for control of exocrine insufficiency, and the use of stenting may play at least a temporizing role. Results secondary to surgery have been promising, with long term success in the 70 to 85% range. Despite surgical procedures, however, the ravages of chronic pancreatitis continue. As fibrosis continues, there is further compromise of exocrine and endocrine function. Cessation of alcohol appears to be a critical adjunct to management of this disease. © 1998 Elsevier Science Inc. MEDICAL UPDATE FOR PSYCHIATRISTS 3;1:7–12, 1998.
Diseases of the pancreas, perhaps more than any other organ, have a tremendous impact on the life of the afflicted individual. The disease is shaped by, and in turn shapes, the behavior of the patient. The relationship of alcohol abuse to chronic pancreatitis has been well documented. The consequence of this disease is disabling pain, with progressive destruction of the gland, and loss of endocrine and exocrine function. Remarkably, many patients do not abandon the behavior patterns that are responsible for their disease. In this article, we define chronic pancreatitis, identify the risk factors for its development, describe the clinical course, and review the latest medical and surgical therapeutic options for the treatment of chronic pancreatitis.
© 1998 Elsevier Science Inc. ISSN 1082-7579/98/$19.00 PII S1082-7579(97)00082-4
Definition and Background
Chronic pancreatitis is a clinical syndrome that is characterized by continuous abdominal pain associated with exocrine or endocrine insufficiency. Chronic pancreatitis is due to progressive destruction of the pancreas from multiple episodes of inflammation. Significant findings are irreversible destruction of pancreatic tissue with acinar loss, shrinkage of glands, fibrosis, calcification, and stricture formation (1,7). The condition is more common than initially recognized and is found in up to 5% of autopsy specimens (3). Chronic pancreatitis occurs in 4 of 100,000 persons per population. The history of chronic pancreatitis goes back to the 17th century. The first report of pancreatic calcifications was in 1667. Baille, in 1799 (1), first described chronic pancreatitis. This description was further characterized by MayoRobson in 1904. Comfort, in 1946, defined chronic pancreatitis as a chronic
Address reprint requests to: Dr. Scott Melvin, Department of Surgery, Ohio State University.
relapsing disease and also recognized its association with alcohol use (6). Anatomy
The adult pancreas is an elongated, flattened, gray-tan organ that extends from the duodenal C loop to the hilum of the spleen (5). Generally, the pancreas weighs between 70 and 120 g, is 12 to 20 cm in length, and lies in the retroperitoneal position. The pancreas has a rich, extensively connected arterial circulation derived from branches of the celiac and superior mesenteric arteries. The remaining blood supply comes from branches of the splenic artery, the dorsal pancreatic, the great pancreatic, and the caudal pancreatic arteries. The venous drainage enters the portal venous system. The lymphatics follow the course of the vessels (5). The innervation of the pancreas is quite complex. Parasympathetic innervation comes through the vagus nerves. Vagal fibers pass through the plexus without synapsing until they reach the parasympathetic ganglia, which are located in the interlobular septae of the pancreas. The postganglionic parasympathetic fibers then supply the acini, ducts, and the islet cells (2). Sympathetic innervation originates in the lateral gray matter of the thoracic spinal cord and synapses in the celiac ganglia. It follows the distribution of the hepatic artery, splenic artery, and superior mesenteric artery and innervates the pancreatic blood vessels. Visceral afferent fibers are carried by the vagi. These fibers travel via the celiac ganglia to the splanchnic nerves in order to reach the thoracic sympathetic chain. From there, they traverse to the spinal root ganglia. These are the fibers that are thought to mediate pain. The exocrine pancreas has two major physiologic functions. The first is intralumenal digestion of macronutrients which occurs through acinar secretion of hydrolytic enzymes resulting in breakdown of fats, proteins, carbohydrates, and nucleic acids. Second, exo-
S. Ikramuddin and W. S. Melvin
crine pancreatic secretions are responsible for the maintenance of nearneutral intralumenal pH with secretion of bicarbonate rich fluid (2). Etiology and Pathogenesis
The major cause of chronic pancreatitis in the Western world is alcoholism. Chronic disease is secondary to alcoholism, whereas recurrent acute attacks of pancreatitis are usually secondary to biliary tract disease. Gallstone disease, itself, rarely leads to chronic pancreatitis. Confirmed alcoholics are 20 to 50 times more likely to suffer from pancreatitis, and alcohol is considered the major etiologic factor in development. In Western societies, alcohol abuse is responsible for approximately 75% cases (1– 4). The pancreas has no threshold for alcohol toxicity. There is no relationship between the type of alcoholic beverage and development of chronic pancreatitis. There appears to be greater sensitivity of the pancreas to alcohol in women. Predisposing factors, in addition to alcohol abuse, include a diet high in protein and high in fat. The development of chronic pancreatitis is logarithmically related to the amount of protein consumption and quadratically related to the amount of fat intake (2). The exact mechanism of pancreatic damage secondary to alcohol is not completely understood. It has been hypothesized that alcohol causes direct damage to acinar cells of the pancreas (3). This induces changes in secretory function with precipitation of enzymatic protein and obstruction of the ducts. A concomitant increase in calcium output has also been noted. The combination of these protein precipitate plugs and calcifications is responsible for the formation of the calcium stones. The stones are typically composed of calcium carbonate and pancreatic stone proteins(PSP) (5,6). The other major subtypes of chronic pancreatitis include tropical pancreatitis, idiopathic pancreatitis, hereditary pancreatitis, and pancreatitis secondary to hyperparathyroidism, pancreas divism, or pancreatic duct obstruction. Tropical pancreatitis is endemic in areas such as Uganda, Kenya, Nigeria, India, Srilanka, or Malaysia. This is a calcific pancreatic disease observed in children (3). It has been associated with extremely low fat intake (4). Predomi-
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nantly, it is found in low income groups within these populations, and malnutrition has been suggested as the etiologic factor. Idiopathic chronic pancreatitis is present in 10 to 30% of patients with chronic pancreatitis. It has a more indolent development than chronic pancreatitis. There is a juvenile and a senile form. The juvenile variety has its onset at about age 25 and has a painful clinical course, whereas, the senile form has a male preponderance with an onset at age 62 (2). Hereditary chronic pancreatitis was first reported in 1952. It has also been associated with a decrease in PSP. The disorder is found in 0.9 to 1.5% of patients with chronic pancreatitis (10). The onset is at a young age, and the disease is propagated in an autosomal dominant fashion, although it has an incomplete genetic penetrance (9). The incidence of hyperparathyroidism associated with chronic pancreatitis has decreased from 5 to 10% to approximately 1.5% of cases (2,15). Other causes include pancreas divism, which is the most frequent ductal anomaly of the pancreas. It occurs when the ventral and dorsal ducts fail to fuse. Chronic pancreatitis occurs with pancreas divisum, but it is uncommon. Chronic pancreatitis may also occur secondary to congenital or acquired stricture of the pancreatic duct. The acquired stricture typically occurs after a bout of chronic pancreatitis, after healing of a pancreatic pseudocyst, or arises from benign tumors in the pancreatic duct. A form of pancreatitis known as ‘‘groove pancreatitis’’ is secondary to formation of a scar between the head of the pancreas and duodenum. Pancreatitis can also be related to other causes such as autoimmune disease (29) and possibly a1-antitrypsin deficiency (17). There is also an association between the O blood group type and chronic pancreatitis. Clinical Features
Chronic pancreatitis presents in males between 40 and 50 years of age (2,3). Symptoms typically occur after 10 to 20 years of ethanol abuse (14). Pain is the most significant clinical finding, and it is the pain that usually brings the patient to clinical attention. Pain can be expected in at least three quarters of patients with pancreatitis (13). In many 8
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studies, it has been noted to be the most common symptom of chronic pancreatitis (2). There are no specific features that can easily distinguish the pain; the pain is often severe, lasts longer, but is less intense then that pain of acute pancreatitis (2). Pain begins approximately 30 min after a meal and may be persistent in nature, similar to the pain of intestinal angina. The pain is located in the mid or left-upper quadrant. It sometimes follows the ingestion of alcohol. Painful attacks occur approximately 12 to 48 h after an episode of drinking. Patients will often try to relieve the pain by flexing the spine. Many theories have been proposed in order to explain the development of pain. One is that pain is due to distention of the pancreatic duct (1), which inturn is secondary to stricture or formation of calculi, although there is no evidence to suggest that elimination of calculi per se will mitigate the pain (5). Strictures are thought to result in increased pancreatic ductal pressure. There is an unclear relationship between increased ductal pressure and pain. In fact, increased ductal pressure is not always documented in chronic pancreatitis. Normal ductal pressure is 7 to 10 mm of mercury. Pressures as high as 48 mm of mercury have been detected with ductal abnormalities in one study (8). A second theory is that nerves are involved by inflammation and scar. There is increased substance P staining in nerve fibers. Increased staining for calcitonin gene related peptide has also been found (1,2). An increased number of eosinophils has been detected in the perineural space. It is important to recognize that the pain of chronic pancreatitis may be associated with other abnormalities, such as development of an extra pancreatic or intra pancreatic pseudocyst. Exocrine pancreatic insufficiency is associated with chronic pancreatitis. This is most severe after resectional treatment for chronic pancreatitis. Exocrine pancreatic insufficiency may result from reduction of enzymes or from failure of activation of enzymes. The pancreas has exocrine reserve, and only when pancreatic lipase and trypsin fall below 10% do the steatorreha or azotorrhea result. Development of a critical deficiency requires at least 10 years in patients with alcoholic disease. Overt
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azotorrhea occurs in 30% of patients with chronic calcific pancreatitis. This may be exacerbated by bacterial overgrowth. Vitamin deficiency of fat soluble vitamins does not usually occur, as there is still some fat absorption. Vitamin B-12 malabsorption can occur due to deficiency of pancreatic protease which is necessary to separate vitamin B-12 from the R-binding protein. This deficiency also occurs over a period of years (3). Endocrine pancreatic insufficiency also occurs, as there is usually concomitant damage of the endocrine and exocrine tissue (2). This is an acquired alpha and beta cell deficiency, although there is less alpha damage. Glucagon is produced by the alpha cells, and, with significant glucagon deficiency, a small amount of insulin causes profound hypoglycemia. Diabetic coma is uncommon in these patients. The incidence of diabetes associated with chronic pancreatitis ranges from 30 to 70% (2). Hypoglycemia occurs uncommonly. Retinopathy, ischemic heart disease, and neuropathy are rare, but these have all been reported. Diabetic glomerulosclerosis is mentioned only in case reports. Other systemic effects of chronic pancreatitis include an increase in blood clotting activity and an increase in gastric acidity (18,19). Diagnosis
The diagnosis of chronic pancreatitis can be strongly suggested by history and physical examination. Patients typically give a history of severe abdominal pain. They are usually pain-medication dependent and give a history of weight loss and steatorrhea. On physical examination, the nutritional state is generally impaired (2). Cachexia, though, is uncommon. One finding known as ‘‘erythema ab igne’’ refers to skin changes in the mid-upper epigastrium, secondary to application of intense heat from heating pads or hot water bottles (2). Laboratory assessment becomes important after identifying significant history and physical findings. Hyperamylasemia can be detected during an exacerbation, but is more commonly found during attacks of acute pancreatitis. Pancreatic insufficiency can be diagnosed using noninvasive tests. These tests look for unabsorbed food or enzymes in the stool. Among these, the
Chronic Pancreatitis: Current Diagnosis and Treatment
fecal-fat test is the most sensitive and specific stool test. Fat output is assessed in the stool over a 72 hour period. Exocrine insufficiency is suspected if 7 grams of fat are excreted after 100 gm. have been ingested over a 24 hour period. Detection of steatorrhea and muscle fibers in the stool is a sensitive but not specific test (3). One can also look for hydrolyzed substances in the urine, blood, or breath. Plasma concentrations of hormones or amino acids can also be detected. Fecal trypsin, fecal chymotrypsin, and the bentridomide test have also been found to be useful. Noninvasive tests involve no risk to the patients, have few side effects, and are easy to perform.. It is important to define endocrine dysfunction in the patient who has exocrine impairment (3). A useful test for this is a two-hour postprandial blood glucose. In one study, 40% of patients were found to be diabetic (1). Computerized axial tomography (CAT) is useful in the diagnosis of chronic pancreatitis and can be used to evaluate other diseases or complications. Ductular findings can be enhanced with secretin. The CAT scan is 75% sensitive (1–3,36). Endoscopic ultrasound (EUS) might be useful to differentiate chronic pancreatitis from cancer. EUS can possibly identify parenchymal changes in the absence of ductular dilatation (12). Endoscopic retrograde cholangiopancreatography (ERCP) remains a useful test in the diagnosis of chronic pancreatitis. It is most useful when there is CAT scan evidence of a dilated pancreatic duct. It should only be performed when discovery of abnormalities will alter management of the patient. Consideration should be given for ERCP when the abdominal pain is intractable or recurrent (2). ERCP is also useful in the presence of a ductal disruption, ductal leak, or in the presence of pleural effusion or ascites associated with chronic pancreatitis. The ERCP is approximately 80 to 90% sensitive (3). Pancreatic ductal manometry has been utilized, but the results have not been uniform. Management
The overall goals of management for chronic pancreatitis include relief of symptoms, prevention of local and regional complications, and an attempt to change the clinical course of the disease 9
(3). Broadly speaking, management can be divided into two categories: medical management and surgical management. Medical management should be attempted first. There are two major goals to medical management, control of pain and control of exocrine/endocrine insufficiency. Management of pain involves control of the acute exacerbations in a similar fashion to acute pancreatitis (2). Non-narcotic analgesics are preferred for management of chronic pain. Codeine, however, can be used in conjunction with acetaminophen. If pain relief does not resolve, then consideration of further workup and possibly surgery must be entertained early in the management of these patients, in order to avoid narcotic addiction. Abstinence from alcohol must be strongly advised to the patient. Cessation of alcohol use reduces exacerbations in up to 50% of patients and slows deterioration of pancreatic function (2,36). Dietary recommendations include limiting fat content in food and frequent, small meals. Oral enzyme treatment for pain control has been suggested. Enzyme treatment is based upon the assumption of feedback regulation of pancreatic secretion (2,3). High intraduodenal peptide levels are thought to inhibit pancreatic enzyme secretion. Inhibition will therefore lead to lower intraductal pressures. Patients with small duct disease may have better reduction in pain (3); however, the preliminary data are mixed. There may be some benefit in patients with moderate disease. Some data suggest that the less severe the pain, the greater the analgesic effect of the pancreatic enzymes (3). Failure to respond to these conservative measures requires further intervention. Percutaneous nerve blocks have been found useful in treating the pain of chronic pancreatitis; however, the pain relief has been short term and limited to a matter of months. Also, a great deal of variability exists in the degree of pain control (37). A percutaneous celiac nerve block can be accomplished using topical anesthetics or neurotoxins. The substance may be administered via a needle under ultrasonic, fluoroscopic, or by CAT guidance (3). Pain relief using this method in patients with pancreatic cancer appears to be associated with better results (3). Management of pancreatic exocrine insufficiency has also received much study. There are a large number of pan-
creatic enzyme products available. It has been determined that approximately 5% to 10% of the level of lipase that is present after maximal pancreatic stimulation is necessary to control symptoms. This corresponds to approximately 30,000 units of lipase. These enzymes are contraindicated in patients with hypersensitivity to porcine products. It is important that the gastric pH be greater than four, otherwise more than 90% of enzymes contained in a capsule or tablet are inactivated in the stomach (3). Increasing the dose of these noncoated enzymes results in nausea, bloating, and abdominal pain. Microsphere preparations which have a pH sensitive covering may have an advantage. Two products are commonly prescribed, pancreatin (Creon, Solvay Pharmaceuticals) and pancrealipase (McNeill Pharmaceuticals) (3). Dietary changes are also useful in patients with enzymatic deficiency. Diets should be small and low in fat. There are some data suggesting that the fat and enzymes should be taken together. Abstention from alcohol allows gastric lipase levels to increase. In patients that have severe steatorrhea, consumption of medium chain triglycerides (fatty acids with 6 to 12 carbons) are required. These are readily hydrolyzed, do not require micelle formation, and the hydrolysed products are absorbed directly. Small amounts of long-chain fatty acids need to be administered in order to prevent essential fatty acid deficiency. Pancreatic endocrine insufficiency is managed with diet and insulin. The daily requirement of insulin is usually 20 to 30 units per day, and the blood glucose is generally kept between 120 to 150 mm. per deciliter. Treatments which are still in their infancy include islet cell transplantation. Surgical management should be entertained after medical management fails or when incompacitating pain develops. A useful initial diagnostic evaluation involves a dynamic CT scan to evaluate the pancreatic duct. Important information is also gained about the viability of the pancreas. If there is no evidence that the duct is enlarged, then an ERCP is performed. The most common problems requiring surgical intervention, in addition to the pain, include distal bile duct obstruction, pseudocysts, colon obstruction, and gastric var-
ices. The primary goal for surgery is to relieve pain and conserve pancreatic function to the greatest extent (34). Historically, a number of operations have been designed for pain control. Current management is directed by the degree of ductal dilatation. If the pancreatic duct is greater than 8 mm in size, then a ductal drainage procedure is carried out. If no demonstrable dilatation is found, then resectional therapy is employed. Usually if a small hard pancreas is identified, then a bilateral splanchnicectomy is performed (1,16). Ductal drainage procedures have undergone a considerable evolution over the past several years. The pancreatic duct is identified, and a roux-en-y pancreaticojejunostomy with mucosal to mucosal anastomosis is preformed. Approximately 15 to 30% patients will fail to obtain any relief. If pain recurs, then a repeat ERCP is performed. Failure to promptly opacify the jejunostomy signifes obstruction and requires revision. Almost 71% of patients will report complete and substantial relief after redrainage procedure. The mortality and morbidity of a redrainage procedure are 7% and 28%, respectively. Complete drainage is the bottom line (1,34). Other alternatives include resection, gangliotomy, and nerve blocks. Cancer and biliary stricture must be considered if recurrent symptoms occur. Local resection with pancreaticojejunostomy (Peustow procedure) may be introduced later. In addition to lateral decompression of the multiply strictured areas of the pancreatic duct, this procedure also provides decompression to the head of the pancreas. The distal portion of the pancreas, including the body and tail, are preserved; this procedure is limited to patients with duct diameter greater than 4.5 mm (34). Beger described a procedure in which the head of the pancreas was resected, leaving a small rim of pancreas attached to the duodenum and the distal portion of the pancreas intact; division of the gland was performed, requiring two anastomoses to restore drainage which was associated with pain relief in 79 to 82% of patients (1,2). Resectional therapy for chronic pancreatitis has been reserved for patients with small ducts. The ‘‘Child procedure,’’ described at the University of Michigan, involves a 95% pancreatectomy, leaving a small rim of pancreas attached to the duode-
num. The reported mortality of this procedure is 3%; pancreatic fistula was the most common complication. The incidence of diabetes approximates 67%. Following this procedure, approximately 50% of patients remain completely pain free, but 25% of patients were left with mild symptoms (1,2,34). The Whipple procedure (pancreaticoduodenectomy) is used when the preponderance of inflammation is found in the head of the pancreas. This procedure may be especially useful in the absence of dilated pancreatic ducts. This procedure is also undertaken with associated biliary or duodenal obstruction. The mortality rate of this procedure ranges between 2% and 15%, but over the past several years has dropped to 1% (34). Long-term results have not shown a significant improvement over nonresectional therapy (32,38). Total pancreatectomy is not commonly performed, and there is an extremely high rate of endocrine abnormalities which appear to affect longevity. Pain relief is not 100%, and, in fact, 34% of patients
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type of pain; long term results are currently pending (35). Long-term Sequelae
There are a number of sequelae of chronic pancreatitis. Pancreatic calcifications are a frequent complication. The percentage varies, but it is very common in alcoholic pancreatitis. At least 55% of patients demonstrate calcifacations on plain films of the abdomen. These calcifications appear 6.8 years earlier in alcoholic patients, compared with patients with idiopathic disease. It is more common in patients with chronic pancreatitis who do not have pain, 70 to 80%. Peptic ulcer disease also co-exists in 6.3 to 37.5% of patients. This may be related to an imbalance of bicarbonate secretion. Splenic changes also occur secondary to the proximity of the pancreas to the spleen. The most common abnormality, splenic vein thrombosis, occurs in 22 to 54% of cases and is observed more commonly in acute pancreatitis (2). In addition, splenic artery pseudoaneurysms have been found associated in 6 to 9.5% of patients with chronic pancreatitis. This is perhaps the most rapidly fatal complication in the event of rupture. In patients who are treated for this condition the mortality rate is approximately 12.5% (24,26). Biliary stricture associated chronic pancreatitis is a significant problem (1). In less than 1% of patients, gastric or duodenal obstruction may occur. Barium swallow or esophagogastroduodenoscopy (EGD) can be used to diagnose this condition. The long constricting lesion of the duodenum is seen in patients with chronic pancreatitis. This condition is best managed with a gastroenterostomy after a period of conservative management. If obstruction is secondary to a pseudocyst, the pseudocyst must be drained first. Pseudocysts are formed by leakage of pancreatic enzymes into the peritoneal cavity where a local inflammatory reaction creates a non-epithelialized cavity. The mechanism varies but usually follows an attack of pancreatitis with extravasation of pancreatic juice. Pseudocysts occur in chronic pancreatitis after ductal obstruction develops. These pseudocysts usually do not resolve spontaneously and require further treatment. Few patients die of chronic pancre-
Chronic Pancreatitis: Current Diagnosis and Treatment
atitis per se; the high death rate in this population is generally linked to the ravages of alcoholism. Disease progression can occur even after the cessation of alcohol. A significant proportion of patients continue to seek alcohol after the development of symptoms. This is not true in patients who develop alcoholic cirrhosis (23). Patients may continue to seek alcohol even following surgery. In fact, alcohol abuse occurs in 42% of patients following lateral pancreaticojejunostomy (20). The clinical course is unpredictable and may burn itself out over a period of 3 to 10 years (3). There are, however, continued reports of pain after 10 years. The risk of pancreatic cancer is up to 5% in patients who have chronic pancreatitis. There is a 2.43 relative risk of developing cancer compared with the overall population (21).
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Morphometric characteristics in adenocarcinoma of the pancreas and chronic pancreatitis. Scand J Gastroenterol. 1994;29:764 – 8. 31. Kukagawa Y, Giaid A, Yanagisawa M, Baynash AG, Melnyk P, Rosenberg L, Duguid WP. Expression of endothelin-1 in pancreatic tissue in patients with chronic pancreatitis. J Pathol. 1996;178:78–83. 32. Suda K, Shiotsu H, Nakamura T. Pancreatic fibrosis in patients with chronic alcohol abuse: correlation with alcoholic pancreatitis. Am J Gastroenterol. 1994; 89:2060 –2. 33. Martin RF, Rossi RL, Leslie KA. Long-term results of pylorus-preserving pancreaticoduodenectomy for
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DEPARTMENT OF SURGERY, DIVISION OF GENERAL SURGERY, OHIO STATE UNIVERSITY, 410 W. 10TH AVENUE, COLUMBUS, OHIO
Abstract
Introduction
Chronic pancreatitis is a disease most commonly caused by alcoholism. It is a disease that manifests itself over the course of 10 to 20 years. It is associated with significant pain and narcotic addiction. Medical treatment appears to be limited, but the use of oral enzyme replacement for control of exocrine insufficiency, and the use of stenting may play at least a temporizing role. Results secondary to surgery have been promising, with long term success in the 70 to 85% range. Despite surgical procedures, however, the ravages of chronic pancreatitis continue. As fibrosis continues, there is further compromise of exocrine and endocrine function. Cessation of alcohol appears to be a critical adjunct to management of this disease. © 1998 Elsevier Science Inc. MEDICAL UPDATE FOR PSYCHIATRISTS 3;1:7–12, 1998.
Diseases of the pancreas, perhaps more than any other organ, have a tremendous impact on the life of the afflicted individual. The disease is shaped by, and in turn shapes, the behavior of the patient. The relationship of alcohol abuse to chronic pancreatitis has been well documented. The consequence of this disease is disabling pain, with progressive destruction of the gland, and loss of endocrine and exocrine function. Remarkably, many patients do not abandon the behavior patterns that are responsible for their disease. In this article, we define chronic pancreatitis, identify the risk factors for its development, describe the clinical course, and review the latest medical and surgical therapeutic options for the treatment of chronic pancreatitis.
© 1998 Elsevier Science Inc. ISSN 1082-7579/98/$19.00 PII S1082-7579(97)00082-4
Definition and Background
Chronic pancreatitis is a clinical syndrome that is characterized by continuous abdominal pain associated with exocrine or endocrine insufficiency. Chronic pancreatitis is due to progressive destruction of the pancreas from multiple episodes of inflammation. Significant findings are irreversible destruction of pancreatic tissue with acinar loss, shrinkage of glands, fibrosis, calcification, and stricture formation (1,7). The condition is more common than initially recognized and is found in up to 5% of autopsy specimens (3). Chronic pancreatitis occurs in 4 of 100,000 persons per population. The history of chronic pancreatitis goes back to the 17th century. The first report of pancreatic calcifications was in 1667. Baille, in 1799 (1), first described chronic pancreatitis. This description was further characterized by MayoRobson in 1904. Comfort, in 1946, defined chronic pancreatitis as a chronic
Address reprint requests to: Dr. Scott Melvin, Department of Surgery, Ohio State University.
relapsing disease and also recognized its association with alcohol use (6). Anatomy
The adult pancreas is an elongated, flattened, gray-tan organ that extends from the duodenal C loop to the hilum of the spleen (5). Generally, the pancreas weighs between 70 and 120 g, is 12 to 20 cm in length, and lies in the retroperitoneal position. The pancreas has a rich, extensively connected arterial circulation derived from branches of the celiac and superior mesenteric arteries. The remaining blood supply comes from branches of the splenic artery, the dorsal pancreatic, the great pancreatic, and the caudal pancreatic arteries. The venous drainage enters the portal venous system. The lymphatics follow the course of the vessels (5). The innervation of the pancreas is quite complex. Parasympathetic innervation comes through the vagus nerves. Vagal fibers pass through the plexus without synapsing until they reach the parasympathetic ganglia, which are located in the interlobular septae of the pancreas. The postganglionic parasympathetic fibers then supply the acini, ducts, and the islet cells (2). Sympathetic innervation originates in the lateral gray matter of the thoracic spinal cord and synapses in the celiac ganglia. It follows the distribution of the hepatic artery, splenic artery, and superior mesenteric artery and innervates the pancreatic blood vessels. Visceral afferent fibers are carried by the vagi. These fibers travel via the celiac ganglia to the splanchnic nerves in order to reach the thoracic sympathetic chain. From there, they traverse to the spinal root ganglia. These are the fibers that are thought to mediate pain. The exocrine pancreas has two major physiologic functions. The first is intralumenal digestion of macronutrients which occurs through acinar secretion of hydrolytic enzymes resulting in breakdown of fats, proteins, carbohydrates, and nucleic acids. Second, exo-
S. Ikramuddin and W. S. Melvin
crine pancreatic secretions are responsible for the maintenance of nearneutral intralumenal pH with secretion of bicarbonate rich fluid (2). Etiology and Pathogenesis
The major cause of chronic pancreatitis in the Western world is alcoholism. Chronic disease is secondary to alcoholism, whereas recurrent acute attacks of pancreatitis are usually secondary to biliary tract disease. Gallstone disease, itself, rarely leads to chronic pancreatitis. Confirmed alcoholics are 20 to 50 times more likely to suffer from pancreatitis, and alcohol is considered the major etiologic factor in development. In Western societies, alcohol abuse is responsible for approximately 75% cases (1– 4). The pancreas has no threshold for alcohol toxicity. There is no relationship between the type of alcoholic beverage and development of chronic pancreatitis. There appears to be greater sensitivity of the pancreas to alcohol in women. Predisposing factors, in addition to alcohol abuse, include a diet high in protein and high in fat. The development of chronic pancreatitis is logarithmically related to the amount of protein consumption and quadratically related to the amount of fat intake (2). The exact mechanism of pancreatic damage secondary to alcohol is not completely understood. It has been hypothesized that alcohol causes direct damage to acinar cells of the pancreas (3). This induces changes in secretory function with precipitation of enzymatic protein and obstruction of the ducts. A concomitant increase in calcium output has also been noted. The combination of these protein precipitate plugs and calcifications is responsible for the formation of the calcium stones. The stones are typically composed of calcium carbonate and pancreatic stone proteins(PSP) (5,6). The other major subtypes of chronic pancreatitis include tropical pancreatitis, idiopathic pancreatitis, hereditary pancreatitis, and pancreatitis secondary to hyperparathyroidism, pancreas divism, or pancreatic duct obstruction. Tropical pancreatitis is endemic in areas such as Uganda, Kenya, Nigeria, India, Srilanka, or Malaysia. This is a calcific pancreatic disease observed in children (3). It has been associated with extremely low fat intake (4). Predomi-
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nantly, it is found in low income groups within these populations, and malnutrition has been suggested as the etiologic factor. Idiopathic chronic pancreatitis is present in 10 to 30% of patients with chronic pancreatitis. It has a more indolent development than chronic pancreatitis. There is a juvenile and a senile form. The juvenile variety has its onset at about age 25 and has a painful clinical course, whereas, the senile form has a male preponderance with an onset at age 62 (2). Hereditary chronic pancreatitis was first reported in 1952. It has also been associated with a decrease in PSP. The disorder is found in 0.9 to 1.5% of patients with chronic pancreatitis (10). The onset is at a young age, and the disease is propagated in an autosomal dominant fashion, although it has an incomplete genetic penetrance (9). The incidence of hyperparathyroidism associated with chronic pancreatitis has decreased from 5 to 10% to approximately 1.5% of cases (2,15). Other causes include pancreas divism, which is the most frequent ductal anomaly of the pancreas. It occurs when the ventral and dorsal ducts fail to fuse. Chronic pancreatitis occurs with pancreas divisum, but it is uncommon. Chronic pancreatitis may also occur secondary to congenital or acquired stricture of the pancreatic duct. The acquired stricture typically occurs after a bout of chronic pancreatitis, after healing of a pancreatic pseudocyst, or arises from benign tumors in the pancreatic duct. A form of pancreatitis known as ‘‘groove pancreatitis’’ is secondary to formation of a scar between the head of the pancreas and duodenum. Pancreatitis can also be related to other causes such as autoimmune disease (29) and possibly a1-antitrypsin deficiency (17). There is also an association between the O blood group type and chronic pancreatitis. Clinical Features
Chronic pancreatitis presents in males between 40 and 50 years of age (2,3). Symptoms typically occur after 10 to 20 years of ethanol abuse (14). Pain is the most significant clinical finding, and it is the pain that usually brings the patient to clinical attention. Pain can be expected in at least three quarters of patients with pancreatitis (13). In many 8
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studies, it has been noted to be the most common symptom of chronic pancreatitis (2). There are no specific features that can easily distinguish the pain; the pain is often severe, lasts longer, but is less intense then that pain of acute pancreatitis (2). Pain begins approximately 30 min after a meal and may be persistent in nature, similar to the pain of intestinal angina. The pain is located in the mid or left-upper quadrant. It sometimes follows the ingestion of alcohol. Painful attacks occur approximately 12 to 48 h after an episode of drinking. Patients will often try to relieve the pain by flexing the spine. Many theories have been proposed in order to explain the development of pain. One is that pain is due to distention of the pancreatic duct (1), which inturn is secondary to stricture or formation of calculi, although there is no evidence to suggest that elimination of calculi per se will mitigate the pain (5). Strictures are thought to result in increased pancreatic ductal pressure. There is an unclear relationship between increased ductal pressure and pain. In fact, increased ductal pressure is not always documented in chronic pancreatitis. Normal ductal pressure is 7 to 10 mm of mercury. Pressures as high as 48 mm of mercury have been detected with ductal abnormalities in one study (8). A second theory is that nerves are involved by inflammation and scar. There is increased substance P staining in nerve fibers. Increased staining for calcitonin gene related peptide has also been found (1,2). An increased number of eosinophils has been detected in the perineural space. It is important to recognize that the pain of chronic pancreatitis may be associated with other abnormalities, such as development of an extra pancreatic or intra pancreatic pseudocyst. Exocrine pancreatic insufficiency is associated with chronic pancreatitis. This is most severe after resectional treatment for chronic pancreatitis. Exocrine pancreatic insufficiency may result from reduction of enzymes or from failure of activation of enzymes. The pancreas has exocrine reserve, and only when pancreatic lipase and trypsin fall below 10% do the steatorreha or azotorrhea result. Development of a critical deficiency requires at least 10 years in patients with alcoholic disease. Overt
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azotorrhea occurs in 30% of patients with chronic calcific pancreatitis. This may be exacerbated by bacterial overgrowth. Vitamin deficiency of fat soluble vitamins does not usually occur, as there is still some fat absorption. Vitamin B-12 malabsorption can occur due to deficiency of pancreatic protease which is necessary to separate vitamin B-12 from the R-binding protein. This deficiency also occurs over a period of years (3). Endocrine pancreatic insufficiency also occurs, as there is usually concomitant damage of the endocrine and exocrine tissue (2). This is an acquired alpha and beta cell deficiency, although there is less alpha damage. Glucagon is produced by the alpha cells, and, with significant glucagon deficiency, a small amount of insulin causes profound hypoglycemia. Diabetic coma is uncommon in these patients. The incidence of diabetes associated with chronic pancreatitis ranges from 30 to 70% (2). Hypoglycemia occurs uncommonly. Retinopathy, ischemic heart disease, and neuropathy are rare, but these have all been reported. Diabetic glomerulosclerosis is mentioned only in case reports. Other systemic effects of chronic pancreatitis include an increase in blood clotting activity and an increase in gastric acidity (18,19). Diagnosis
The diagnosis of chronic pancreatitis can be strongly suggested by history and physical examination. Patients typically give a history of severe abdominal pain. They are usually pain-medication dependent and give a history of weight loss and steatorrhea. On physical examination, the nutritional state is generally impaired (2). Cachexia, though, is uncommon. One finding known as ‘‘erythema ab igne’’ refers to skin changes in the mid-upper epigastrium, secondary to application of intense heat from heating pads or hot water bottles (2). Laboratory assessment becomes important after identifying significant history and physical findings. Hyperamylasemia can be detected during an exacerbation, but is more commonly found during attacks of acute pancreatitis. Pancreatic insufficiency can be diagnosed using noninvasive tests. These tests look for unabsorbed food or enzymes in the stool. Among these, the
Chronic Pancreatitis: Current Diagnosis and Treatment
fecal-fat test is the most sensitive and specific stool test. Fat output is assessed in the stool over a 72 hour period. Exocrine insufficiency is suspected if 7 grams of fat are excreted after 100 gm. have been ingested over a 24 hour period. Detection of steatorrhea and muscle fibers in the stool is a sensitive but not specific test (3). One can also look for hydrolyzed substances in the urine, blood, or breath. Plasma concentrations of hormones or amino acids can also be detected. Fecal trypsin, fecal chymotrypsin, and the bentridomide test have also been found to be useful. Noninvasive tests involve no risk to the patients, have few side effects, and are easy to perform.. It is important to define endocrine dysfunction in the patient who has exocrine impairment (3). A useful test for this is a two-hour postprandial blood glucose. In one study, 40% of patients were found to be diabetic (1). Computerized axial tomography (CAT) is useful in the diagnosis of chronic pancreatitis and can be used to evaluate other diseases or complications. Ductular findings can be enhanced with secretin. The CAT scan is 75% sensitive (1–3,36). Endoscopic ultrasound (EUS) might be useful to differentiate chronic pancreatitis from cancer. EUS can possibly identify parenchymal changes in the absence of ductular dilatation (12). Endoscopic retrograde cholangiopancreatography (ERCP) remains a useful test in the diagnosis of chronic pancreatitis. It is most useful when there is CAT scan evidence of a dilated pancreatic duct. It should only be performed when discovery of abnormalities will alter management of the patient. Consideration should be given for ERCP when the abdominal pain is intractable or recurrent (2). ERCP is also useful in the presence of a ductal disruption, ductal leak, or in the presence of pleural effusion or ascites associated with chronic pancreatitis. The ERCP is approximately 80 to 90% sensitive (3). Pancreatic ductal manometry has been utilized, but the results have not been uniform. Management
The overall goals of management for chronic pancreatitis include relief of symptoms, prevention of local and regional complications, and an attempt to change the clinical course of the disease 9
(3). Broadly speaking, management can be divided into two categories: medical management and surgical management. Medical management should be attempted first. There are two major goals to medical management, control of pain and control of exocrine/endocrine insufficiency. Management of pain involves control of the acute exacerbations in a similar fashion to acute pancreatitis (2). Non-narcotic analgesics are preferred for management of chronic pain. Codeine, however, can be used in conjunction with acetaminophen. If pain relief does not resolve, then consideration of further workup and possibly surgery must be entertained early in the management of these patients, in order to avoid narcotic addiction. Abstinence from alcohol must be strongly advised to the patient. Cessation of alcohol use reduces exacerbations in up to 50% of patients and slows deterioration of pancreatic function (2,36). Dietary recommendations include limiting fat content in food and frequent, small meals. Oral enzyme treatment for pain control has been suggested. Enzyme treatment is based upon the assumption of feedback regulation of pancreatic secretion (2,3). High intraduodenal peptide levels are thought to inhibit pancreatic enzyme secretion. Inhibition will therefore lead to lower intraductal pressures. Patients with small duct disease may have better reduction in pain (3); however, the preliminary data are mixed. There may be some benefit in patients with moderate disease. Some data suggest that the less severe the pain, the greater the analgesic effect of the pancreatic enzymes (3). Failure to respond to these conservative measures requires further intervention. Percutaneous nerve blocks have been found useful in treating the pain of chronic pancreatitis; however, the pain relief has been short term and limited to a matter of months. Also, a great deal of variability exists in the degree of pain control (37). A percutaneous celiac nerve block can be accomplished using topical anesthetics or neurotoxins. The substance may be administered via a needle under ultrasonic, fluoroscopic, or by CAT guidance (3). Pain relief using this method in patients with pancreatic cancer appears to be associated with better results (3). Management of pancreatic exocrine insufficiency has also received much study. There are a large number of pan-
creatic enzyme products available. It has been determined that approximately 5% to 10% of the level of lipase that is present after maximal pancreatic stimulation is necessary to control symptoms. This corresponds to approximately 30,000 units of lipase. These enzymes are contraindicated in patients with hypersensitivity to porcine products. It is important that the gastric pH be greater than four, otherwise more than 90% of enzymes contained in a capsule or tablet are inactivated in the stomach (3). Increasing the dose of these noncoated enzymes results in nausea, bloating, and abdominal pain. Microsphere preparations which have a pH sensitive covering may have an advantage. Two products are commonly prescribed, pancreatin (Creon, Solvay Pharmaceuticals) and pancrealipase (McNeill Pharmaceuticals) (3). Dietary changes are also useful in patients with enzymatic deficiency. Diets should be small and low in fat. There are some data suggesting that the fat and enzymes should be taken together. Abstention from alcohol allows gastric lipase levels to increase. In patients that have severe steatorrhea, consumption of medium chain triglycerides (fatty acids with 6 to 12 carbons) are required. These are readily hydrolyzed, do not require micelle formation, and the hydrolysed products are absorbed directly. Small amounts of long-chain fatty acids need to be administered in order to prevent essential fatty acid deficiency. Pancreatic endocrine insufficiency is managed with diet and insulin. The daily requirement of insulin is usually 20 to 30 units per day, and the blood glucose is generally kept between 120 to 150 mm. per deciliter. Treatments which are still in their infancy include islet cell transplantation. Surgical management should be entertained after medical management fails or when incompacitating pain develops. A useful initial diagnostic evaluation involves a dynamic CT scan to evaluate the pancreatic duct. Important information is also gained about the viability of the pancreas. If there is no evidence that the duct is enlarged, then an ERCP is performed. The most common problems requiring surgical intervention, in addition to the pain, include distal bile duct obstruction, pseudocysts, colon obstruction, and gastric var-
ices. The primary goal for surgery is to relieve pain and conserve pancreatic function to the greatest extent (34). Historically, a number of operations have been designed for pain control. Current management is directed by the degree of ductal dilatation. If the pancreatic duct is greater than 8 mm in size, then a ductal drainage procedure is carried out. If no demonstrable dilatation is found, then resectional therapy is employed. Usually if a small hard pancreas is identified, then a bilateral splanchnicectomy is performed (1,16). Ductal drainage procedures have undergone a considerable evolution over the past several years. The pancreatic duct is identified, and a roux-en-y pancreaticojejunostomy with mucosal to mucosal anastomosis is preformed. Approximately 15 to 30% patients will fail to obtain any relief. If pain recurs, then a repeat ERCP is performed. Failure to promptly opacify the jejunostomy signifes obstruction and requires revision. Almost 71% of patients will report complete and substantial relief after redrainage procedure. The mortality and morbidity of a redrainage procedure are 7% and 28%, respectively. Complete drainage is the bottom line (1,34). Other alternatives include resection, gangliotomy, and nerve blocks. Cancer and biliary stricture must be considered if recurrent symptoms occur. Local resection with pancreaticojejunostomy (Peustow procedure) may be introduced later. In addition to lateral decompression of the multiply strictured areas of the pancreatic duct, this procedure also provides decompression to the head of the pancreas. The distal portion of the pancreas, including the body and tail, are preserved; this procedure is limited to patients with duct diameter greater than 4.5 mm (34). Beger described a procedure in which the head of the pancreas was resected, leaving a small rim of pancreas attached to the duodenum and the distal portion of the pancreas intact; division of the gland was performed, requiring two anastomoses to restore drainage which was associated with pain relief in 79 to 82% of patients (1,2). Resectional therapy for chronic pancreatitis has been reserved for patients with small ducts. The ‘‘Child procedure,’’ described at the University of Michigan, involves a 95% pancreatectomy, leaving a small rim of pancreas attached to the duode-
num. The reported mortality of this procedure is 3%; pancreatic fistula was the most common complication. The incidence of diabetes approximates 67%. Following this procedure, approximately 50% of patients remain completely pain free, but 25% of patients were left with mild symptoms (1,2,34). The Whipple procedure (pancreaticoduodenectomy) is used when the preponderance of inflammation is found in the head of the pancreas. This procedure may be especially useful in the absence of dilated pancreatic ducts. This procedure is also undertaken with associated biliary or duodenal obstruction. The mortality rate of this procedure ranges between 2% and 15%, but over the past several years has dropped to 1% (34). Long-term results have not shown a significant improvement over nonresectional therapy (32,38). Total pancreatectomy is not commonly performed, and there is an extremely high rate of endocrine abnormalities which appear to affect longevity. Pain relief is not 100%, and, in fact, 34% of patients
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type of pain; long term results are currently pending (35). Long-term Sequelae
There are a number of sequelae of chronic pancreatitis. Pancreatic calcifications are a frequent complication. The percentage varies, but it is very common in alcoholic pancreatitis. At least 55% of patients demonstrate calcifacations on plain films of the abdomen. These calcifications appear 6.8 years earlier in alcoholic patients, compared with patients with idiopathic disease. It is more common in patients with chronic pancreatitis who do not have pain, 70 to 80%. Peptic ulcer disease also co-exists in 6.3 to 37.5% of patients. This may be related to an imbalance of bicarbonate secretion. Splenic changes also occur secondary to the proximity of the pancreas to the spleen. The most common abnormality, splenic vein thrombosis, occurs in 22 to 54% of cases and is observed more commonly in acute pancreatitis (2). In addition, splenic artery pseudoaneurysms have been found associated in 6 to 9.5% of patients with chronic pancreatitis. This is perhaps the most rapidly fatal complication in the event of rupture. In patients who are treated for this condition the mortality rate is approximately 12.5% (24,26). Biliary stricture associated chronic pancreatitis is a significant problem (1). In less than 1% of patients, gastric or duodenal obstruction may occur. Barium swallow or esophagogastroduodenoscopy (EGD) can be used to diagnose this condition. The long constricting lesion of the duodenum is seen in patients with chronic pancreatitis. This condition is best managed with a gastroenterostomy after a period of conservative management. If obstruction is secondary to a pseudocyst, the pseudocyst must be drained first. Pseudocysts are formed by leakage of pancreatic enzymes into the peritoneal cavity where a local inflammatory reaction creates a non-epithelialized cavity. The mechanism varies but usually follows an attack of pancreatitis with extravasation of pancreatic juice. Pseudocysts occur in chronic pancreatitis after ductal obstruction develops. These pseudocysts usually do not resolve spontaneously and require further treatment. Few patients die of chronic pancre-
Chronic Pancreatitis: Current Diagnosis and Treatment
atitis per se; the high death rate in this population is generally linked to the ravages of alcoholism. Disease progression can occur even after the cessation of alcohol. A significant proportion of patients continue to seek alcohol after the development of symptoms. This is not true in patients who develop alcoholic cirrhosis (23). Patients may continue to seek alcohol even following surgery. In fact, alcohol abuse occurs in 42% of patients following lateral pancreaticojejunostomy (20). The clinical course is unpredictable and may burn itself out over a period of 3 to 10 years (3). There are, however, continued reports of pain after 10 years. The risk of pancreatic cancer is up to 5% in patients who have chronic pancreatitis. There is a 2.43 relative risk of developing cancer compared with the overall population (21).
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14. 15.
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Morphometric characteristics in adenocarcinoma of the pancreas and chronic pancreatitis. Scand J Gastroenterol. 1994;29:764 – 8. 31. Kukagawa Y, Giaid A, Yanagisawa M, Baynash AG, Melnyk P, Rosenberg L, Duguid WP. Expression of endothelin-1 in pancreatic tissue in patients with chronic pancreatitis. J Pathol. 1996;178:78–83. 32. Suda K, Shiotsu H, Nakamura T. Pancreatic fibrosis in patients with chronic alcohol abuse: correlation with alcoholic pancreatitis. Am J Gastroenterol. 1994; 89:2060 –2. 33. Martin RF, Rossi RL, Leslie KA. Long-term results of pylorus-preserving pancreaticoduodenectomy for
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