PANCREATITIS

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GASTROENTEROLOGY

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PAPJCREATITIS Evaluation and Treatment Gerald C. Dragonetti, MD, Harvey Licht, MD, and Walter Rubin, MD

Acute and chronic pancreatitis are challenging diseases for the general physician. They must be diagnosed accurately, and their specific causes identified. Their prognoses and expected courses must be appreciated, and their multiple, often serious complications recognized. In this way the physician can institute proper therapies in a timely fashion so as to minimize mortality and morbidity, prevent recurrent disease, optimally preserve pancreatic function, maintain optimal nutrition, and correct the serious, often life-threatening complications. The general physician also should know when to seek help from the gastroenterologist or surgeon when managing difficult patients with these diseases. Acute pancreatitis usually resolves, and pancreatic function is preserved adequately. The inflammatory process of chronic pancreatitis, however, often destroys much more of the organ and its normal functioning, frequently leaving the patient with pancreatic endocrine or exocrine insufficiency.

ACUTE PANCREATITIS

The pathology and severity of acute pancreatitis vary from mild edematous pancreatitis to severe hemorrhagic pancreatitis. Edematous pancreatitis is an inflammatory process in which there is no evidence of pancreatic necrosis on CT scan. In the more severe necrotizing pancreatitis, the inflammation leads to necrosis of pancreatic tissue. This can be From the Division of Gastroenterology, Department of Medicine, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania PRIMARY CARE VOLUME 23 * NUMBER 3 SEPTEMBER 1996

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complicated further by hemorrhage or sometimes by the colonization of the necrotic tissue by bacteria and the formation of an abscess. Etiology The most frequent causes of acute pancreatitis are gallstones and chronic use of alcohol. Many other less common causes are listed in Table 1. Alcoholic pancreatitis develops after continuous and long-term inges-

Table 1. CAUSES OF ACUTE PANCREATITIS Alcohol Gallstones Postoperative Postendoscopicretrograde cholangiopancreatography (ERCP) Trauma Metabolic causes Hypertriglyceridemia Apolipoprotein C-ll deficiency syndrome Hypercalcemia Renal failure 7. Hereditary pancreatitis 8. Infections Mumps Viral hepatitis Coxsackievirus Ascariasis Mycoplasma 9. Drug-induced Azathioprine Sulfonamides Thiazide diuretics Furosemide (Lasix) Estrogens Tetracycline Valproic acid Pentamidine Dideoxyinosine 10. Connective tissue disorders Systemic lupus erythematosus Necrotizing angiitis Thrombotic thrombocytopenic purpura 11. Penetrating peptic ulcer 12. Obstruction of the ampulla of Vater Regional enteritis Duodenal diverticulum 13. Pancreas divisum 14. Cystic fibrosis 15. Sphincter of Oddi dysfunction 16. Pancreatic cancer 17. Idiopathic 1. 2. 3. 4. 5. 6.

Adapted from Wilson JD, Braunwald E, et al: Acute and chronic pancreatitis. In Harrison’s Principles of Internal Medicine, ed 12. New York, McGraw-Hill, 1991, p 1374; with permission.

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tion of alcohol, typically occurring after 8 to 10 years.2Data are insufficient to assess the quantity of alcohol required to cause pancreatitis; however, if alcoholic liver disease is used as a comparison, more than 80 to 100 g of daily consumption of alcohol is necessary.37 Diagnosis

The diagnosis of acute pancreatitis is made by a constellation of findings, including clinical history, physical examination, serum enzyme assays, and, when necessary, radiologic tests. The clinical manifestations of acute pancreatitis are varied. One of the most common symptoms is epigastric pain, which is characteristically steady and often radiates to the back. Nausea and vomiting are frequent accompanying symptoms. Fever may be present, but the temperature is rarely greater than 102". Because of the local inflammatory process, patients may have accompanying ileus. Although infrequent, a pleural effusion may occur, usually on the left side, but sometimes on the right or both sides. There may be findings of an acute abdomen, such as rebound tenderness and guarding. Shock can accompany pancreatitis and may be on the basis of hemorrhage or fluid sequestration within the inflamed pancreatic bed or abdomen or from the release of vasodilator substances. In patients with severe hemorrhagic pancreatitis, fulminant disease may ensue with marked hemodynamic instability. Patients with hemorrhagic pancreatitis may have a light blue discoloration around the umbilicus (Cullen's sign) or a red-blue discoloration of the flanks (Grey Turner's sign) secondary to extraperitoneal blood. Laboratory tests are useful in the diagnosis and prognosis of patients with acute pancreatitis. Serum amylase and lipase levels are the major diagnostic tests of acute pancreatitis, and they usually rise within 48 hours of the development of pancreatitis and return to normal within 1 week. Other conditions, however, such as intestinal obstruction, ischemia, or perforation also may raise these enzyme^.^,^^ An elevated amylase also may be associated with an ectopic pregnancy in a fallopian tube, macroamylasemia, parotitis, and renal failure.'* The degree of elevation of the amylase and lipase does not correlate with the severity of pan~reatitis.'~ Comparing changes in absolute values of amylase and lipase during the course of the illness, therefore, is not clinically useful.35The persistence of an elevated amylase for more than 7 days, however, suggests continued inflammation with possible development of a phlegmon or a pseudocyst. Liver enzyme tests may be useful in suggesting the cause of acute pancreatitis, especially in the case of gallstone pancreatitis. An acute elevation in the serum transaminase levels with a concomitant rise in the serum alkaline-phosphatase and frequently the bilirubin may be seen with a common duct stone.32In patients with pancreatitis, the liver function tests may be elevated secondary to concomitant alcoholic liver disease or from a swollen pancreatic head pressing on the common bile duct. Radiology may be useful in the diagnosis of pancreatitis. In a patient

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with abdominal pain and suspected acute pancreatitis, an abdominal obstruction series may exclude other causes of pain such as intestinal obstruction or perforation. Pancreatitis may be associated with a generalized or localized ileus. A dilated loop of small bowel in the left upper quadrant, a so-called sentinel loop, may be observed. Films also may reveal gastric distention or a colon cut-off sign, which is lack of gas beyond the midtransverse colon. These signs represent localized atony of the intestine adjacent to areas of pancreatic inflammation. Ultrasound may show an enlarged pancreas, which in edematous pancreatitis is homogeneous without abnormal echogenicity. One of its most important uses is in evaluating the biliary system for stones or bile duct dilatation, which may suggest choledocholithiasis as a cause of the pancreatitis. Ultrasound is also useful to diagnose a pseudocyst. The use of CT in the evaluation of patients with acute pancreatitis should not be routine. In patients with uncomplicated acute pancreatitis it is not necessary to obtain a study to visualize the pancreas. CT is helpful, however, in a patient suspected of having a complication such as phlegmon, pseudocyst, pancreatic necrosis, hemorrhage, or pancreatic abscess.4J9The CT finding suggestive of pancreatic necrosis is lack of enhancement with intravenous contrast dye.6Pancreatic abscess may appear as single or multiple fluid collections. Gas within the pancreas usually is caused by bacteria and is diagnostic of an

Prognosis

The assessment of prognosis in patients with acute pancreatitis is based on several clinical and laboratory criteria. The most widely used classification was proposed by Ranson.' This scheme uses data from admission and again 2 days later. At admission the factors that have been observed empirically to be associated with a poor prognosis include age older than 55, white blood count greater than 16,000, lactate dehydrogenase greater than 350 U/mL, aspartate aminotransferase greater than 250 U/L, and serum glucose greater than 200 mg/dL. After 48 hours additional parameters, based on physiologic abnormalities, again assess the severity of disease. Hypoxemia with a Po, less than 60 mm Hg may indicate acute respiratory distress syndrome. An increase in blood urea nitrogen greater than 5 mg/dL may signify the presence of acute tubular necrosis. Patients with pancreatitis initially are dehydrated and have an elevated blood urea nitrogen. After volume repletion, the blood urea nitrogen is expected to decrease; however, a paradoxic rise suggests the development of acute tubular necrosis. A base deficit greater than 4 mEq/L, fluid sequestration greater than 6 L, and calcium less than 8 mg/dL are other findings associated with a poor prognosis. A decrease in hematocrit by greater than 10 suggests the presence of hemorrhagic pancreatitis. Smaller decreases can be expected after hydration of the patient, who often is hemoconcentrated on admission because of volume depletion.'

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Complications

A pseudocyst, a common complication of pancreatitis, is a cystic space that is enclosed by a fibrous capsule and contains fluid consisting of pancreatic enzymes and necrotic pancreatic debris. An acute pseudoPseudocyst develops within 3 weeks of the onset of acute pancreatiti~.~ cysts typically are diagnosed when an acute episode of pancreatitis persists and a patient is evaluated for prolonged Complications of pseudocysts include infection with abscess formation, rupture leading to acute peritonitis, or fistulization with the formation of pancreatic ascites or pleural effusi0n.3~ A pseudocyst also can cause compression of adjacent structures leading to obstruction of the stomach, duodenum, colon, or common bile duct. Erosion into surrounding vessels can lead to hemorrhage within the cyst and is manifested as a fall in hemoglobin and hemodynamic instability associated with an expanding mass within the abdomen. This can be confirmed with CT scan or angiography if suspected. A second complication of pancreatitis is infection. Bacterial infection can arise within a necrotic pancreas or within a pseudocyst, giving rise to an abscess. Persistent fever or leukocytosis in a patient with an inflammatory mass documented by CT scan raises the clinical suspicion of pancreatic abscess. Sterile necrosis also may be associated with these findings. Aspiration of the mass and a Gram’s stain and culture of its contents differentiate these two conditions. A pancreatic abscess requires antibiotics and drainage to decrease the high mortality associated with this complication.16A patient who has evidence of clinical deterioration secondary to sterile necrotizing pancreatitis also may benefit from surgical debridement, h ~ w e v e r . ~ Treatment

The treatment for patients with mild pancreatitis is primarily supportive and includes intravenous fluids and medication for pain. Classically, physicians have tried to put the pancreas at rest by reducing all stimuli of pancreatic secretion. By means of nasogastric suction and the elimination of oral feedings, stimulation of the pancreas by cholecystokinin, secretin, and the vagus nerves theoretically is reduced. Nasogastric suction does not reduce mortality or decrease length of hospitalization, however, although it may be useful in relieving pain, nausea, vomiting, and i l e u ~ . ~ * , ~ ~ H,-blockers and glucagon also have been used to decrease pancreatic stimulation and, it is hoped, to reduce morbidity and mortality. H,-blockers should reduce the secretion of secretin by inhibiting gastric acid secretion, and glucagon directly suppresses pancreatic exocrine secretion. Neither of these agents, however, seems effective in altering the course of pancreatiti~.~~ More recently, octreotide, an analog of somatostatin, has been used to inhibit pancreatic secretion; its potential value is not clear. Management of pancreatitis also includes close monitoring of com-

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plications and their early and vigorous treatment. Hemodynamics and urine output should be watched closely because intravascular volume may be depleted severely.28Hypoxia and hypocalcemia must be recognized early and treated appropriately. Routine use of antibiotics in acute pancreatitis is not recommended except in the case of suspected or documented pancreatic infection or if cholangitis is suspected when choledocholithiasis is believed to be the cause of the pancreatitis.l0 In the treatment of gallstone pancreatitis, when a retained common duct stone is suspected to be the cause of an unremitting, severe clinical course, a timely endoscopic retrograde cholangiopancreatography(ERCP) with sphincterotomyand stone extraction may be helpful. Elevated serum bilirubin, alkaline phosphatase, and transaminases; a dilated common bile duct; or cholangitis may suggest the presence of the stone. Patients with gallstone pancreatitis experience frequent recurrences of acute pancreatitis as well as other complications of gallstones such as cholangitis or acute chole~ystitis.'~ Surgery is indicated therefore to prevent these recurrences and complications. Because cholecystectomy performed early in the course of severe gallstone pancreatitis is associated with an increased morbidity, these patients may be better treated initially with endoscopic sphincterotomy and removal of common bile duct ~ t o n e s . ' ~ , ~ ~ Apparent pseudocysts should be observed for at least 6 to 8 weeks before surgery. During this time some apparent pseudocysts, especially small ones, will disappear, whereas the true ones will mature, making them more amenable to drainage. Surgical drainage is performed to alleviate any symptoms and to reduce the risks of complication of the pseudocyst, such as infection,bleeding, or r u p t ~ r e . *Some , ~ ~ ,pseudocysts ~~ may be drained percutaneously or even endoscopically.

CHRONIC PANCREATITIS Although chronic, often disabling pain is usually the most prominent symptom of chronic pancreatitis, patients often suffer various degrees of pancreatic endocrine (diabetes) or exocrine (maldigestion and malabsorption) insufficiency. The most common cause of chronic pancreatitis in adults is alcohol. In children and adolescents, cystic fibrosis and hereditary pancreatitis are more common causes.27In approximately 25% of adults with chronic pancreatitis the cause is unknown and is considered idiopathic. The pattern of pain in patients with chronic pancreatitis is variable. Patients may have continuous chronic pain, or they may experience recurrent episodes of acute pain, similar to that of acute pancreatitis.13

Diagnosis and Complications Chronic pancreatitis may be diagnosed in many ways. Some patients have endocrine insufficiency and diabetes. Some patients may exhibit exocrine insufficiency, manifested by the malabsorption of fat resulting in diarrhea, steatorrhea, and weight loss. Excessive stool fat can be detected

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by qualitative analysis, but a quantitative analysis can assess the amount of steatorrhea present. These patients also may malabsorb and become deficient in fat soluble vitamins. In a patient with fat malabsorption, the clinical response to an empiric trial with pancreatic enzyme supplements may be used as a confirmation of chronic pancreatitis and pancreatic insufficiency.26 Additional tests to evaluate pancreatic exocrine function include the secretin-cholecystokinin test and bentiromide test. Secretin stimulates secretion of water and bicarbonate from the pancreas, and cholecystokinin stimulates pancreatic enzyme release. By administering these hormones and then measuring the pancreatic secretions from the duodenum, a reliable assessment of pancreatic function can be made. Bentiromide is a synthetic peptide that is cleaved enzymatically into para-amino benzoic acid by the pancreatic enzyme chymotrypsin. Paraaminobenzoic acid is absorbed in the intestine, conjugated in the liver, and excreted in the urine. Patients with chronic pancreatitis and pancreatic exocrine insufficiency will have an abnormal bentiromide test. The test, however, may be falsely positive in patients with an abnormality in intestinal mucosal absorption or with liver or kidney disease.I4 Other laboratory tests may be useful in the diagnosis of chronic pancreatitis. The serum amylase may be normal or e l e ~ a t e dAn . ~ elevation of serum bilirubin and alkaline phosphatase and possibly a dilated common bile duct uncommonly are seen secondary to bile duct stricture from chronic inflammation or bile duct obstruction from a fibrosed pancreatic head or a pseudocyst. Radiologic studies also can suggest a diagnosis of chronic pancreatitis. In patients with alcoholic pancreatitis, calcification of the pancreas, revealed by a plain abdominal film or CT scan, is diagnostic of chronic pancreatitis when pre~ent.’~ Pancreatic calcification also may occur with hyperparathyroidism. CT scan also may reveal splenomegaly secondary to splenic vein thrombosis, a rare complication of chronic pancreatitis. ERCP may reveal a dilated or strictured pancreatic duct and blunting of smaller ducts, abnormalities also suggestive of chronic pancreatitis. ERCP usually is not necessary for diagnosis, however. Pseudocyst may complicate chronic pancreatitis and has the same potential complications as in acute pancreatitis, such as infection, hemorrhage, and rupture. Occasionally a fistula may extend from a pseudocyst or pancreatic duct to the pleural or peritoneal space. This presents with symptoms attributable to ascites or pleural effusion, such as abdominal distention or shortness of breath. These patients may not have a history of abdominal pain and therefore may not be suspected of having chronic pancreatitis before this complication. The diagnosis is suggested by analysis of the ascitic or pleural fluid, which is exudative and contains a greatly elevated aiyiylase Treatment

Medical treatment of chronic pancreatitis usually is directed toward relief of symptoms and complications.Abstinence from alcohol is essential

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in preventing further bouts of pancreatitis and may be helpful in reducing pain. Pancreatic enzyme replacement is necessary to treat exocrine insufficiency. Daily supplements should be used with each meal. The use of enzyme supplements decreases the amount of steatorrhea and diarrhea and should lead to weight gain. An occasional patient may have a reduction in pain when given pancreatic enzyme replacement. This treatment is thought to reduce the stimulation of pancreatic secretion by a negative feedback mechanism.22Dietary treatment includes providing a high calorie, low-fat diet, supplemented with fat soluble vitamins. Total parenteral nutrition occasionally may be necessary in patients who have a pancreatic fistula, protracted pain, or ileus. Narcotics may be necessary for pain control. Short-term inhibition of pancreatic secretion with the use of octreotide has not been shown to relieve pain in chronic pancreatitis, although it may be useful when treating a fistula.20 The surgical management of chronic pancreatitis is reserved for specific circumstances.For relief of chronic, intractable pain that has not been relieved with medical therapy, surgery may be an option. Surgery usually is not effective if the patient continues to drink alcohol. Neurosurgical or injection procedures to interrupt pain pathways usually provide only temporary relief. In patients with chronic pain who have evidence of pancreatic duct stricture and dilatation, pancreaticojejunostomy (Puestow procedure) permits drainage of the pancreatic duct into the jejunum. Resection of various amounts of pancreas is another surgical option. Local resections for local disease such as distal pancreatectomy may be effective in selected cases, but radical resections such as subtotal and total pancreatectomies generally have been disappointing. These surgical procedures may provide short-term control of pain, but long-term relief occurs less frequently. In addition, pancreatectomy frequently causes diabetes and malabsorption. Surgical drainage of a pseudocyst may relieve pain and prevent or treat complications such as rupture, infection, obstruction, or h e m ~ r r h a g e .Some ~ ~ , ~pseudocysts ~ may be drained into the stomach or duodenum by means of stents placed endoscopically. Endoscopically placed stents also may be used to bridge ductal disruptions that are the cause of pancreatic ascites.17 Partial obstruction of the common bile duct by a stricture, an inflamed, fibrosed pancreatic head, or a pseudocyst must be recognized and treated. The obstruction may be suggested by an elevated serum alkaline phosphatase or by ductal dilatation observed by ultrasonography or CT scan. ERCP may be required to localize and define the obstruction. Patients with a common bile duct obstruction require decompression to prevent secondary biliary cirrhosis or cholangitis. Pseudocysts may be drained. Strictures and other obstructions may be bypassed surgically with a choledochojejunostomy.ERCP also can be used to dilate a stricture or to place a stent to relieve the o b s t r ~ c t i o n . ' ~ , ~ ~ SUMMARY

Acute and chronic pancreatitis present challenging problems for the physician. In acute pancreatitis, initial efforts should be directed toward

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supporting the patient hemodynamically. Recognition and early treatment of complications such as shock, renal failure, respiratory failure, hypocalcemia, abscess, hemorrhage, or unremitting symptoms caused by an impacted stone in the common bile duct are necessary. The cause of the pancreatitis must be identified, possibly for acute therapy, but certainly to prevent recurrences and progression of disease. In chronic pancreatitis, insufficiencies of pancreatic function must be identified and consequent malabsorption and diabetes treated appropriately. The major challenge is the relief of chronic pain. It is hoped that this can be accomplished medically, but in carefully selected cases, specific types of surgery may be required.

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24. Moosa AR Surgical treatment of chronic pancreatitis: An overview. Br J Surg 74:661, 1987 25. Neoptolemos JP, Carr-Locke D, London NJ, et al: Controlled trial of urgent ERCP and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet 979, 1988 26. kederau C, Grendell JH: Diagnosis of chronic pancreatitis. Gastroenterology 88:1973, 1985 27. Perrault J: Hereditary pancreatitis. Gastroenterol Clin North Am 23:743, 1994 28. Regan PT Medical treatment of acute pancreatitis. Mayo Clin Proc 54:432,1979 29. Regan PT, Malagelada J, Go VL, et a1 A prospective study of the antisecretory and therapeutic effects of cimetidine and glucagon in human acute pancreatitis. Mayo Clin Proc 56499,1981 30. Rockey DC, Cello JP: Pancreaticopleural fistula. Medicine 69:332,1990 31. Sanfey H, Aguilar M, Jones RS,et al: Pseudocysts of the pancreas, a review of 97 cases. Am Surgeon 9667,1994 32. Shemsh E, et al: Choledocholithiasis: A comparison between the clinical presentations of multiple and solitary stones in the common bile duct. Am J Gastroenterol 84:1055, 1989 33. Soergel K H Medical treatment of acute pancreatitis. What is the evidence? Gastroenterology 74620,1978 34. Stanten R, Frey CF: Comprehensive management of acute necrotizing pancreatitis and pancreatic abscess. Arch Surg 125:1269,1990 35. Ventrucci M, Pezzilli R, Gullo L, et al: Role of serum pancreatic enzyme assays in diagnosis of pancreatic disease. Dig Dis Sci 34:39,1989 36. Warshaw AL, Jin G: Improved survival in 45 patients with pancreatic abscess. Ann Surg 202:408, 1985 37. Wilson JS, Bemstein L, McDonald C, et al: Diet and drinking habits in relation to the development of alcoholic pancreatitis. Gut 26:882,1985

Address reprint requests to Gerald C. Dragonetti, MD Division of Gastroenterology Allegheny University of the Health Sciences 3300 Henry Avenue Philadelphia, PA 19129