Acute and Chronic Pancreatitis
Biochemistry and Physiology of Pancreatic Exocrine Secretion
The pancreas secretes 1500 to 3000 mL of isosmotic alkaline (pH >8.0) fluid per day containing about 20 enzymes and zymogens. The pancreatic secretions provide the enzymes needed to effect the major digestive activity of the gastrointestinal tract and provide an optimal pH for the function of these enzymes.
Regulation of Pancreatic Secretion
The exocrine pancreas is influenced by intimately interacting hormonal and neural systems. Gastric acid is the stimulus for the release of secretin, a peptide with 27 amino acids. Sensitive radioimmunoassay studies for secretin suggest that the pH threshold for its release from the duodenum and jejunum is 4.5. Secretin stimulates the secretion of pancreatic juice rich in water and electrolytes. Release of cholecystokinin (CCK) from the duodenum and jejunum is largely triggered by long-chain fatty acids, certain essential amino acids (tryptophan, phenylalanine, valine, methionine), and gastric acid itself. CCK evokes an enzyme-rich secretion from the pancreas. Gastrin, although it has the same terminal tetrapeptide as CCK, is a weak stimulus for pancreatic enzyme output. The parasympathetic nervous system (via the vagus nerve) exerts significant control over pancreatic secretion. Secretion evoked by secretin and CCK depends on permissive roles of vagal afferent and efferent pathways. This is particularly true for enzyme secretion, whereas water and bicarbonate secretion is heavily dependent on the hormonal effects of secretin and CCK. Also, vagal stimulation effects the release of vasoactive intestinal peptide (VIP), a secretin agonist. Bile salts also stimulate pancreatic secretion, thereby integrating the functions of the biliary tract, pancreas, and small intestine.
Somatostatin acts on multiple sites to induce inhibition of pancreatic secretion. The appropriate roles of other peptides, such as peptide YY, pancreastatin, gastrin-releasing peptide, pituitary adenylate cyclase-activating polypeptide, calcitonin gene-related peptide, and galanin are still being defined. Nitric oxide is an important neurotransmitter in the regulation of pancreatic exocrine secretion, although its mechanism of action has not been fully elucidated.
Water and Electrolyte Secretion
Although sodium, potassium, chloride, calcium, zinc, phosphate, and sulfate are found in pancreatic secretions, bicarbonate is the ion of primary physiologic importance. In the acini and in the ducts, secretin causes the cells to add water and bicarbonate to the fluid. In the ducts, an exchange occurs between bicarbonate and chloride. There is a good correlation between the maximal bicarbonate output after stimulation with secretin and the pancreatic mass. The bicarbonate output of 120 to 300 mmol/d helps neutralize gastric acid and creates the appropriate pH for the activity of the pancreatic enzymes.
The pancreas secretes amylolytic, lipolytic, and proteolytic enzymes. Amylolytic enzymes, such as amylase, hydrolyze starch to oligosaccharides and to the disaccharide maltose. The lipolytic enzymes include lipase, phospholipase A, and cholesterol esterase. Bile salts inhibit lipase in isolation; but colipase, another constituent of pancreatic secretion, binds to lipase and prevents this inhibition. Bile salts activate phospholipase A and cholesterol esterase. Proteolytic enzymes include endopeptidases (trypsin, chymotrypsin), which act on internal peptide bonds of proteins and polypeptides; exopeptidases (carboxypeptidases, aminopeptidases), which act on the free carboxyl- and amino-terminal ends of peptides, respectively; and elastase. The proteolytic enzymes are secreted as inactive precursors (zymogens). Ribonucleases (deoxyribonucleases, ribonuclease) are also secreted. Although pancreatic enzymes usually are secreted in parallel, nonparallel secretion can occur as a result of exocytosis from heterogeneous sources in the pancreas. Enterokinase, an enzyme found in the duodenal mucosa, cleaves the lysine-isoleucine bond of trypsinogen to form trypsin. Trypsin then activates the other proteolytic zymogens in a cascade phenomenon. All pancreatic enzymes have pH optima in the alkaline range.
Autoprotection of the Pancreas
Autodigestion of the pancreas is prevented by the packaging of proteases in precursor form and by the synthesis of protease inhibitors. These protease inhibitors are found in the acinar cell, the pancreatic secretions, and the alpha1- and alpha2-globulin fractions of plasma.
Insulin appears to be needed locally for secretin and CCK to promote exocrine secretion; thus, it acts in a permissive role for these two hormones.
Enteropancreatic Axis and Feedback Inhibition
Pancreatic enzyme secretion is controlled, at least in part, by a negative feedback mechanism induced by the presence of active serine proteases in the duodenum. To illustrate, perfusion of the duodenal lumen with phenylalanine causes a prompt increase in plasma CCK levels as well as increased secretion of chymotrypsin. However, simultaneous perfusion with trypsin blunts both responses. Conversely, perfusion of the duodenal lumen with protease inhibitors actually leads to enzyme hypersecretion. The available evidence supports the concept that the duodenum contains a peptide called CCK releasing factor (CCK-RF) that is involved in stimulating CCK release. Two peptides, luminal CCK-RF and diazepam-binding inhibitor, have been found that may be the CCK-RF. Serine proteases inhibit pancreatic secretion by acting on CCK-RF. It appears that serine proteases inhibit pancreatic secretion by acting on a CCK-releasing peptide in the lumen of the small intestine.
Pancreatic inflammatory disease may be classified as (1) acute pancreatitis and (2) chronic pancreatitis. The pathologic spectrum of acute pancreatitis varies from edematous pancreatitis, which is usually a mild and self-limited disorder, to necrotizing pancreatitis, in which the degree of pancreatic necrosis correlates with the severity of the attack and its systemic manifestations. The term hemorrhagic pancreatitis is less meaningful in a clinical sense because variable amounts of interstitial hemorrhage can be found in pancreatitis as well as in other disorders such as pancreatic trauma, pancreatic carcinoma, and severe congestive heart failure.
incidence of pancreatitis varies in different countries and depends on cause,
e.g., alcohol, gallstones, metabolic factors, and drugs (Table 304-1). In the
Etiology and Pathogenesis
There are many causes of acute pancreatitis (Table 304-1), but the mechanisms by which these conditions trigger pancreatic inflammation have not been identified. Alcoholic patients with pancreatitis may represent a special subset, since most alcoholics do not develop pancreatitis. The list of identifiable causes is growing, and it is likely that pancreatitis related to viral infections, drugs, and as yet undefined factors is more common than heretofore recognized.
Approximately 2 to 5% of cases of acute pancreatitis are drug-related (Table 304-1). Drugs cause pancreatitis either by a hypersensitivity reaction or by the generation of a toxic metabolite, although in some cases it is not clear which of these mechanisms is operative.
Autodigestion is one pathogenetic theory, according to which pancreatitis results when proteolytic enzymes (e.g., trypsinogen, chymotrypsinogen, proelastase, and phospholipase A) are activated in the pancreas rather than in the intestinal lumen. A number of factors (e.g., endotoxins, exotoxins, viral infections, ischemia, anoxia, and direct trauma) are believed to activate these proenzymes. Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but also can activate other enzymes, such as elastase and phospholipase. The active enzymes then digest cellular membranes and cause proteolysis, edema, interstitial hemorrhage, vascular damage, coagulation necrosis, fat necrosis, and parenchymal cell necrosis. Cellular injury and death result in the liberation of activated enzymes. In addition, activation and release of bradykinin peptides and vasoactive substances (e.g., histamine) are believed to produce vasodilation, increased vascular permeability, and edema. Thus, a cascade of events culminates in the development of acute necrotizing pancreatitis.
The autodigestion theory has largely eclipsed two older theories. First, according to the "common channel" theory, the existence of a common anatomic channel for pancreatic secretions and bile permits reflux of bile into the pancreatic duct, which results in activation of pancreatic enzymes. (Actually, a common channel with free communication between the common bile duct and the main pancreatic duct is infrequently encountered.) The second theory is that obstruction and hypersecretion are pivotal in the development of pancreatitis. Obstruction of the main pancreatic duct, however, produces pancreatic edema but generally not pancreatitis.
A recent hypothesis to explain the intrapancreatic activation of zymogens is that they become activated by lysosomal hydrolases in the pancreatic acinar cell itself. In two different types of experimental pancreatitis, it has been demonstrated that digestive enzymes and lysosomal hydrolases become admixed; as a result, the latter can activate the former in the acinar cell. In vitro, lysosomal enzymes such as cathepsin B can activate trypsinogen, and trypsin can activate the other protease precursors. It is still not clear, however, whether the human acinar cell can provide the pH (about 3.0) necessary for activation of trypsinogen by lysosomal hydrolases. It is now believed that ischemia/hypoperfusion can alone result in activation of trypsinogen and pancreatic injury.
Abdominal pain is the major symptom of acute pancreatitis. Pain may vary from a mild and tolerable discomfort to severe, constant, and incapacitating distress. Characteristically, the pain, which is steady and boring in character, is located in the epigastrium and periumbilical region and often radiates to the back as well as to the chest, flanks, and lower abdomen. The pain is frequently more intense when the patient is supine, and patients often obtain relief by sitting with the trunk flexed and knees drawn up. Nausea, vomiting, and abdominal distention due to gastric and intestinal hypomotility and chemical peritonitis are also frequent complaints.
Physical examination frequently reveals a distressed and anxious patient. Low-grade fever, tachycardia, and hypotension are fairly common. Shock is not unusual and may result from (1) hypovolemia secondary to exudation of blood and plasma proteins into the retroperitoneal space (a "retroperitoneal burn"); (2) increased formation and release of kinin peptides, which cause vasodilation and increased vascular permeability; and (3) systemic effects of proteolytic and lipolytic enzymes released into the circulation. Jaundice occurs infrequently; when present, it usually is due to edema of the head of the pancreas with compression of the intrapancreatic portion of the common bile duct. Erythematous skin nodules due to subcutaneous fat necrosis may occur. In 10 to 20% of patients, there are pulmonary findings, including basilar rales, atelectasis, and pleural effusion, the latter most frequently left-sided. Abdominal tenderness and muscle rigidity are present to a variable degree, but, compared with the intense pain, these signs may be unimpressive. Bowel sounds are usually diminished or absent. A pancreatic pseudocyst may be palpable in the upper abdomen. A faint blue discoloration around the umbilicus (Cullen's sign) may occur as the result of hemoperitoneum, and a blue-red-purple or green-brown discoloration of the flanks (Turner's sign) reflects tissue catabolism of hemoglobin. The latter two findings, which are uncommon, indicate the presence of a severe necrotizing pancreatitis.
The diagnosis of acute pancreatitis is usually established by the detection of an increased level of serum amylase. Values threefold or more above normal virtually clinch the diagnosis if overt salivary gland disease and gut perforation or infarction are excluded. However, there appears to be no definite correlation between the severity of pancreatitis and the degree of serum amylase elevation. After 48 to 72 h, even with continuing evidence of pancreatitis, total serum amylase values tend to return to normal. However, pancreatic isoamylase and lipase levels may remain elevated for 7 to 14 days. It will be recalled that amylase elevations in serum and urine occur in many conditions other than pancreatitis (see Table 303-2). Importantly, patients with acidemia (arterial pH 7.32) may have spurious elevations in serum amylase. In one study, 12 of 33 patients with acidemia had elevated serum amylase, but only 1 had an elevated lipase value; in 9, salivary-type amylase was the predominant serum isoamylase. This finding explains why patients with diabetic ketoacidosis may have marked elevations in serum amylase without any other evidence of acute pancreatitis. Serum lipase activity increases in parallel with amylase activity, and measurement of both enzymes increases the diagnostic yield. An elevated serum lipase or trypsin value is usually diagnostic of acute pancreatitis; these tests are especially helpful in patients with nonpancreatic causes of hyperamylasemia (see Table 303-2). Markedly increased levels of peritoneal or pleural fluid amylase [>1500 nmol/L (> 5000 U/dL)] are also helpful, if present, in establishing the diagnosis.
Leukocytosis (15,000 to 20,000 leukocytes per microliter) occurs frequently. Patients with more severe disease may show hemoconcentration with hematocrit values exceeding 50% because of loss of plasma into the retroperitoneal space and peritoneal cavity. Hyperglycemia is common and is due to multiple factors, including decreased insulin release, increased glucagon release, and an increased output of adrenal glucocorticoids and catecholamines. Hypocalcemia occurs in approximately 25% of patients, and its pathogenesis is incompletely understood. Although earlier studies suggested that the response of the parathyroid gland to a decrease in serum calcium is impaired, subsequent observations have failed to confirm this idea. Intraperitoneal saponification of calcium by fatty acids in areas of fat necrosis occurs occasionally, with large amounts (up to 6.0 g) dissolved or suspended in ascitic fluid. Such "soap formation" also may be significant in patients with pancreatitis, mild hypocalcemia, and little or no obvious ascites. Hyperbilirubinemia [serum bilirubin >68 mol/L (> 4.0 mg/dL)] occurs in approximately 10% of patients. However, jaundice is transient, and serum bilirubin levels return to normal in 4 to 7 days. Serum alkaline phosphatase and aspartate aminotransferase (AST) levels are also transiently elevated and parallel serum bilirubin values. Markedly elevated serum lactic dehydrogenase (LDH) levels [>8.5 mol/L (> 500 U/dL)] suggest a poor prognosis. Serum albumin is decreased to 30 g/L (3.0 g/dL) in about 10% of patients; this sign is associated with more severe pancreatitis and a higher mortality rate (Table 304-2). Hypertriglyceridemia occurs in 15 to 20% of patients, and serum amylase levels in these individuals are often spuriously normal (Chap. 303). Most patients with hypertriglyceridemia and pancreatitis, when subsequently examined, show evidence of an underlying derangement in lipid metabolism which probably antedated the pancreatitis (see below). Approximately 25% of patients have hypoxemia (arterial PO2 60 mmHg), which may herald the onset of acute respiratory distress syndrome. Finally, the electrocardiogram is occasionally abnormal in acute pancreatitis with ST-segment and T-wave abnormalities simulating myocardial ischemia.
Although one or more radiologic abnormalities are found in over 50% of patients, the findings are inconstant and nonspecific. The chief value of conventional x-rays [chest films; kidney, ureter, and bladder (KUB) studies] in acute pancreatitis is to help exclude other diagnoses, especially a perforated viscus. Upper gastrointestinal tract x-rays have been superseded by ultrasonography and computed tomography (CT). A CT scan may confirm the clinical impression of acute pancreatitis even in the face of normal serum amylase levels. Importantly, CT is quite helpful in indicating the severity of acute pancreatitis and the risk of morbidity and mortality (see below). Sonography and radionuclide scanning [N-p-isopropylacetanilide-iminodiacetic acid (PIPIDA) scan; hepatic 2,6-dimethyliminodiacetic acid (HIDA) scan] are useful in acute pancreatitis to evaluate the gallbladder and biliary tree. Radiologic 303 and 303-1.
Any severe acute pain in the abdomen or back should suggest acute pancreatitis. The diagnosis is usually entertained when a patient with a possible predisposition to pancreatitis presents with severe and constant abdominal pain, nausea, emesis, fever, tachycardia, and abnormal findings on abdominal examination. Laboratory studies frequently reveal leukocytosis, an abnormal appearance on x-rays of the abdomen and chest, hypocalcemia, and hyperglycemia. The diagnosis is usually confirmed by the finding of an elevated level of serum amylase and/or lipase. Not all the above features have to be present for the diagnosis to be established.
The differential diagnosis should include the following disorders: (1) perforated viscus, especially peptic ulcer; (2) acute cholecystitis and biliary colic; (3) acute intestinal obstruction; (4) mesenteric vascular occlusion; (5) renal colic; (6) myocardial infarction; (7) dissecting aortic aneurysm; (8) connective tissue disorders with vasculitis; (9) pneumonia; and (10) diabetic ketoacidosis. A penetrating duodenal ulcer usually can be identified by upper gastrointestinal x-rays and/or endoscopy. A perforated duodenal ulcer is readily diagnosed by the presence of free intraperitoneal air. It may be difficult to differentiate acute cholecystitis from acute pancreatitis, since an elevated serum amylase may be found in both disorders. Pain of biliary tract origin is more right-sided and gradual in onset, and ileus is usually absent; sonography and radionuclide scanning are helpful in establishing the diagnosis of cholelithiasis and cholecystitis. Intestinal obstruction due to mechanical factors can be differentiated from pancreatitis by the history of colicky pain, findings on abdominal examination, and x-rays of the abdomen showing changes characteristic of mechanical obstruction. Acute mesenteric vascular occlusion is usually evident in elderly debilitated patients with brisk leukocytosis, abdominal distention, and bloody diarrhea, in whom paracentesis shows sanguineous fluid and arteriography shows vascular occlusion. Serum as well as peritoneal fluid amylase levels are increased, however, in patients with intestinal infarction. Systemic lupus erythematosus and polyarteritis nodosa may be confused with pancreatitis, especially since pancreatitis may develop as a complication of these diseases. Diabetic ketoacidosis is often accompanied by abdominal pain and elevated total serum amylase levels, thus closely mimicking acute pancreatitis. However, the serum lipase and pancreatic isoamylase levels are not elevated in diabetic ketoacidosis.
Course of the Disease and Complications
It is important to identify patients with acute pancreatitis who have an increased risk of dying. Ranson and Imrie have used multiple prognostic criteria and have demonstrated that there is an increased mortality rate when three or more risk factors are identifiable either at the time of admission to the hospital or during the initial 48 h of hospitalization (Table 304-2). Recent studies indicate that obesity is a major risk factor for severe pancreatitis, presumably because the increased deposits of peripancreatic fat in such patients may predispose them to more extensive pancreatic and peripancreatic necrosis. The acute physiology and chronic health evaluation scoring system (APACHE II) uses the worst values of 12 physiologic measurements plus age and previous health status and provides a good description of illness severity for a wide range of common diseases; this score also correlates with outcome. Prospective studies have compared APACHE II with multiple prognostic criteria, i.e., Ranson and Imrie scores, in predicting the severity of acute pancreatitis. On admission, APACHE II identified approximately two-thirds of severe attacks, and after 48 h, the prognostic accuracy of APACHE II is comparable with that of Ranson and Imrie's scoring system. The drawbacks of APACHE II are (1) its complexity, (2) the requirement of a computer for scoring, and (3) standardization regarding peak values and cutoff scores. McMahon and colleagues have shown that the presence of a "toxic broth" or dark (hemorrhagic) fluid in abdominal pancreatitis is also an important prognostic indicator in acute pancreatitis. These multiple-factor scoring systems are difficult to use and have not been embraced consistently by clinicians. There is a great need for a reliable, simple biochemical test that consistently predicts outcome in patients with acute pancreatitis. Three candidate markers that show great promise are C-reactive protein, serum granulocyte elastase, and urinary trypsinogen activation peptide (TAP). The key indicators of a severe attack of acute pancreatitis are also listed in Table 304-2. Importantly, the presence of any one of these factors is associated with an increased risk of complications, and the presence of any two, with a 20 to 30% mortality rate. The high mortality rate of such severely ill patients is due in large part to infection and warrants intensive radiologic intervention and monitoring and/or a combination of radiologic and surgical means, as discussed in detail below.
The local and systemic complications of acute pancreatitis are listed in Table 304-3. In the first 2 to 3 weeks after pancreatitis patients frequently develop an inflammatory mass, which may be due to pancreatic necrosis (with or without infection) or may represent an abscess or pseudocyst (see below). Systemic complications include pulmonary, cardiovascular, hematologic, renal, metabolic, and central nervous system abnormalities. Pancreatitis and hypertriglyceridemia constitute an association in which cause and effect remain incompletely understood. However, several reasonable conclusions can be drawn. First, hypertriglyceridemia can precede and apparently cause pancreatitis. Second, the vast majority (>80%) of patients with acute pancreatitis do not have hypertriglyceridemia. Third, almost all patients with pancreatitis and hypertriglyceridemia have preexisting abnormalities in lipoprotein metabolism. Fourth, many of the patients with this association have persistent hypertriglyceridemia after recovery from pancreatitis and are prone to recurrent episodes of pancreatitis. Fifth, any factor (e.g., drugs or alcohol) that causes an abrupt increase in serum triglycerides to levels greater than 11 mmol/L (1000 mg/dL) can precipitate a bout of pancreatitis that can be associated with significant complications and even become fulminant. To avert the risk of triggering pancreatitis, a fasting serum triglyceride measurement should be obtained before estrogen replacement therapy is begun in postmenopausal women. Fasting levels less than 300 mg/dL pose no risk, whereas levels greater than 750 mg/dL are associated with a high probability of developing pancreatitis. Finally, patients with a deficiency of apolipoprotein CII have an increased incidence of pancreatitis; apolipoprotein CII activates lipoprotein lipase, which is important in clearing chylomicrons from the bloodstream.
Purtscher's retinopathy, a relatively unusual complication, is manifested by a sudden and severe loss of vision in a patient with acute pancreatitis. It is characterized by a peculiar funduscopic appearance with cotton-wool spots and hemorrhages confined to an area limited by the optic disk and macula; it is believed to be due to occlusion of the posterior retinal artery with aggregated granulocytes.
The two most common causes of acute pancreatitis are alcoholism and biliary tract disease; other causes are listed in Table 304-1. The risk of acute pancreatitis in patients with at least one gallstone smaller than 5 mm in diameter is fourfold greater than that in patients with larger stones. However, after a conventional workup, a specific cause is not identified in about 30% of patients. It is important to note that ultrasound examinations fail to detect gallstones, especially microlithiasis and/or sludge, in 4 to 7% of patients. In one series of 31 patients diagnosed initially as having idiopathic acute pancreatitis, 23 were found to have occult gallstone disease. Thus, approximately two-thirds of patients with recurrent acute pancreatitis without an obvious cause actually have occult gallstone disease due to microlithiasis. Examination of duodenal aspirates in such cases often reveals cholesterol crystals, which confirm the diagnosis. Other diseases of the biliary tree and pancreatic ducts that can cause acute pancreatitis include choledochocele, ampullary tumors, pancreas divisum, and pancreatic duct stones, stricture, and tumor. Approximately 2% of patients with pancreatic carcinoma present with acute pancreatitis.
Pancreatitis in Patients with AIDS
The incidence of acute pancreatitis is increased in patients with AIDS for two reasons: (1) the high incidence of infections involving the pancreas, such as infections with cytomegalovirus, Cryptosporidium, and the Mycobacterium avium complex; and (2) the frequent use by patients with AIDS of medications such as didanosine, pentamidine, and trimethoprim-sulfamethoxazole (Chap. 309).
In most patients (approximately 85 to 90%) with acute pancreatitis, the disease is self-limited and subsides spontaneously, usually within 3 to 7 days after treatment is instituted. Conventional measures include (1) analgesics for pain, (2) intravenous fluids and colloids to maintain normal intravascular volume, (3) no oral alimentation, and (4) nasogastric suction to decrease gastrin release from the stomach and prevent gastric contents from entering the duodenum. Recent controlled trials, however, have shown that nasogastric suction offers no clear-cut advantages in the treatment of mild to moderately severe acute pancreatitis. Its use, therefore, must be considered elective rather than mandatory.
It has been demonstrated that CCK-stimulated pancreatic secretion is almost abolished in four different experimental models of acute pancreatitis. This finding probably explains why drugs to block pancreatic secretion in acute pancreatitis have failed to have any therapeutic benefit. For this and other reasons, anticholinergic drugs are not indicated in acute pancreatitis. In addition to nasogastric suction and anticholinergic drugs, other therapies designed to "rest the pancreas" by inhibiting pancreatic secretion have not changed the course of the disease. Although antibiotics have been used in the treatment of acute pancreatitis, randomized, prospective trials have shown no benefit from their use in acute pancreatitis of mild to moderate severity.
However, current experimental evidence favors the use of prophylactic antibiotics in severe acute pancreatitis. Results of four contemporary randomized clinical trials restricted to patients with prognostically severe acute pancreatitis have demonstrated an improved outcome, i.e., reduced rate of infection and/or mortality, associated with the antibiotic treatment. The carbapenem group of antibiotics, including imipenem, has a very broad spectrum including activity against Pseudomonas, Staphylococcus, and Enterococcus; and these agents penetrate well into pancreatic tissue. Furthermore, because secondary infection of necrotic pancreatic tissue (abscess, pseudocyst or obstructed biliary passages, ascending cholangitis complicating choledocholithiasis) contributes to many of the late deaths from pancreatitis, appropriate antibiotic therapy of established infections is quite important.
Several other drugs have been evaluated by prospective controlled trials and found ineffective in the treatment of acute pancreatitis. The list, by no means complete, includes glucagon, H2 blockers, protease inhibitors such as aprotinin, glucocorticoids, calcitonin, nonsteroidal anti-inflammataory drugs (NSAIDs) and lexiplafant, a platelet-activating factor inhibitor. A recent meta-analysis of somatostatin, ocreotide, and the antiprotease gabexate methylate in therapy of acute pancreatitis suggested (1) a reduced mortality rate but no change in complications with octreotide, and (2) no effect on the mortality rate but reduced pancreatic damage with gabexate.
Intraabdominal Candida infection during acute necrotizing pancreatitis is increasing in frequency and is associated with an increased mortality rate. In one representatitve trial, intraabdominal Candida infection was found in 13 of 37 cases and was associated with a mortality rate fourfold greater than that associated with intraabdominal bacterial infection alone. Given the impact of Candida infection on the mortality rate in acute necrotizing pancreatitis and the apparent benefit of prophylactic chemotherapy, these data suggest earlier use of fungicides.
A CT scan, especially a contrast-enhanced dynamic CT (CECT) scan, provides valuable information on the severity and prognosis of acute pancreatitis (Fig. 304-1 and Table 304-4). In particular, a CECT scan allows estimation of the presence and extent of pancreatic necrosis. Recent studies suggest that the likelihood of prolonged pancreatitis or a serious complication is negligible when the CT severity index is 1 or 2 and low with scores of 3 to 6. However, patients with scores of 7 to 10 had a 92% morbidity rate and a 17% mortality rate. Necrosis is present in 20 to 30% of patients. Those with necrosis have a morbidity rate >20%, whereas those without necrosis have a morbidity rate <10% and a negligible mortality rate. A CECT scan is indicated in patients with three or more of Ranson's signs, in all seriously ill patients, and in patients who show evidence of clinical deterioration. The patient with mild to moderate pancreatitis usually requires treatment with intravenous fluids, fasting, and possibly nasogastric suction for 2 to 4 days. A clear liquid diet is frequently started on the third to sixth day, and a regular diet by the fifth to seventh day. The patient with unremitting fulminant pancreatitis usually requires inordinate amounts of fluid and close attention to complications such as cardiovascular collapse, respiratory insufficiency, and pancreatic infection. The latter should be managed by a combination of radiologic and surgical means (see below). While earlier uncontrolled studies suggested that peritoneal lavage through a percutaneous dialysis catheter was helpful in severe pancreatitis, subsequent studies indicate that this treatment does not influence the outcome of such attacks. Aggressive surgical pancreatic debridement (necrosectomy) should be undertaken soon after confirmation of the presence of infected necrosis, and multiple operations may be required. Since the mortality rate from sterile acute necrotizing pancreatitis is approximately 10%, laparotomy with adequate drainage and removal of necrotic tissue should be considered if conventional therapy does not halt the patient's deterioration. The use of parenteral nutrition makes it possible to give nutritional support to patients with severe, acute, or protracted pancreatitis who are unable to eat normally. Patients with severe gallstone-induced pancreatitis may improve dramatically if papillotomy is carried out within the first 36 to 72 h of the attack. Studies indicate that only those patients with gallstone pancreatitis who are in the very severe group should be considered for urgent endoscopic retrograde cholangiopancreatography (ERCP). Finally, the treatment for patients with hypertriglyceridemia-associated pancreatitis includes (1) weight loss to ideal weight, (2) a lipid-restricted diet, (3) exercise, (4) avoidance of alcohol and of drugs that can elevate serum triglycerides (i.e., estrogens, vitamin A, thiazides, and beta-blockers), and (5) control of diabetes.
Infected Pancreatic Necrosis, Abscess, and Pseudocyst
Infected pancreatic necrosis should be differentiated from pancreatic abscess. The former is a diffuse infection of an acutely inflamed, necrotic pancreas occurring in the first 1 to 2 weeks after the onset of pancreatitis. In contrast, a pancreatic abscess is an ill-defined, liquid collection of pus that evolves over a longer period, often 4 to 6 weeks. It tends to be less life-threatening and is associated with a lower rate of surgical mortality. Infected pancreatic necrosis should be treated by surgical debridement because the solid component of the infected pancreas is not amenable to effective radiologically guided percutaneous evacuation. Pancreatic abscess can be treated surgically or, in selected cases, by percutaneous drainage. The necrotic pancreas becomes secondarily infected in 40 to 60% of patients, most frequently with gram-negative bacteria of alimentary origin. Whether infection occurs depends on several factors, including the extent of pancreatic and peripancreatic necrosis, the degree of pancreatic ischemia and hypoperfusion, and the presence of organ or multiorgan failure.
The early diagnosis of pancreatic infection can be accomplished by CT-guided needle aspiration. In one study, 60 patients, representing 5% of all admissions for acute pancreatitis, were suspected of harboring a pancreatic infection on the basis of fever, leukocytosis, and an abnormal CT scan (pseudocyst or extrapancreatic fluid collection). Importantly, 60% of these patients had a pancreatic infection, and 55% of these infections developed in the first 2 weeks. These findings suggest that only guided aspiration can reliably distinguish sterile from infected pancreatic necrosis. The following are guidelines for patients meeting the above selection criteria: (1) Pseudocysts should be aspirated promptly, because more than half may be infected; (2) extrapancreatic fluid collections need not be aspirated promptly, because most are sterile; (3) if a necrotic pancreas is found initially to be sterile but fever and leukocytosis persist, several days of observation should be allowed to pass before reaspiration is considered, as clinical improvement frequently occurs; and (4) if fever and leukocytosis recur after an interval of well-being, reaspiration should be considered.
Severe pancreatitis with the presence of three or more risk factors, postoperative pancreatitis, early oral feeding, early laparotomy, and perhaps injudicious use of antibiotics predispose to the development of pancreatic abscess, which occurs in 3 to 4% of patients with acute pancreatitis. Pancreatic abscess also may develop because of a communication between a pseudocyst and the colon, inadequate surgical drainage of a pseudocyst, or needling of a pseudocyst. The characteristic signs of abscess are fever, leukocytosis, ileus, and rapid deterioration in a patient previously recovering from pancreatitis. Sometimes, however, the only manifestations are persistent fever and signs of continuing pancreatic inflammation. Drainage of pancreatic abscesses by percutaneous catheter techniques, using CT guidance, has been only moderately successful (resolution in 50 to 60% of patients). Accordingly, laparotomy with radical sump drainage and possibly resection of necrotic tissue is usually required, because the mortality rate for undrained pancreatic abscess approaches 100%. Multiple abscesses are common, and reoperation is frequently necessary.
Pseudocysts of the pancreas are collections of tissue, fluid, debris, pancreatic enzymes, and blood which develop over a period of 1 to 4 weeks after the onset of acute pancreatitis; they form in approximately 15% of patients with acute pancreatitis. In contrast to true cysts, pseudocysts do not have an epithelial lining; their walls consist of necrotic tissue, granulation tissue, and fibrous tissue. Disruption of the pancreatic ductal system is common. However, the subsequent course of this disruption varies widely, ranging from spontaneous healing to continuous leakage of pancreatic juice, which results in tense ascites. Pseudocysts are preceded by pancreatitis in 90% of cases and by trauma in 10%. Approximately 85% are located in the body or tail of the pancreas and 15% in the head. Some patients have two or more pseudocysts. Abdominal pain, with or without radiation to the back, is the usual presenting complaint. A palpable, tender mass may be found in the middle or left upper abdomen. The serum amylase level is elevated in 75% of patients at some point during their illness and may fluctuate markedly.
On x-ray examination, 75% of pseudocysts can be seen to displace some portion of the gastrointestinal tract (Fig. 304-2). Sonography, however, is reliable in detecting pseudocysts. Sonography also permits differentiation between an edematous, inflamed pancreas, which can give rise to a palpable mass, and an actual pseudocyst. Furthermore, serial ultrasound studies will indicate whether a pseudocyst has resolved. CT complements ultrasonography in the diagnosis of pancreatic pseudocyst (Fig. 304-2), especially when the pseudocyst is infected.
In studies with sonography, pseudocysts were seen to resolve in 25 to 40% of patients. Pseudocysts that are greater than 5 cm in diameter and that persist for longer than 6 weeks should be considered for drainage. Recent natural history studies have suggested that noninterventional, expectant management is the best course in selected patients with minimal symptoms and no evidence of active alcohol use in whom the pseudocyst appears mature by radiography and does not resemble a cystic neoplasm. A significant number of these pseudocysts resolve spontaneously more than 6 weeks after their formation. Also, these studies demonstrate that large pseudocyst size is not an absolute indication for interventional therapy and that many peripancreatic fluid collections detected on CT in cases of acute pancreatitis resolve spontaneously. A pseudocyst that does not resolve spontaneously may lead to serious complications, such as (1) pain caused by expansion of the lesion and pressure on other viscera, (2) rupture, (3) hemorrhage, and (4) abscess. Rupture of a pancreatic pseudocyst is a particularly serious complication. Shock almost always supervenes, and mortality rates range from 14% if the rupture is not associated with hemorrhage to over 60% if hemorrhage has occurred. Rupture and hemorrhage are the prime causes of death from pancreatic pseudocyst. A triad of findings-an increase in the size of the mass, a localized bruit over the mass, and a sudden decrease in hemoglobin level and hematocrit without obvious external blood loss-should alert one to the possibility of hemorrhage from a pseudocyst. Thus, in patients who are stable and free of complications and in whom serial ultrasound studies show that the pseudocyst is shrinking, conservative therapy is indicated. Conversely, if the pseudocyst is expanding and is complicated by rupture, hemorrhage, or abscess, the patient should be operated on. With ultrasound or CT guidance, sterile chronic pseudocysts can be treated safely with single or repeated needle aspiration or more prolonged catheter drainage with a success rate of 45 to 75%. The success rate of these techniques for infected pseudocysts is considerably less (40 to 50%). Patients who do not respond to drainage require surgical therapy for internal or external drainage of the cyst.
Pseudoaneurysms develop in up to 10% of patients with acute pancreatitis at sites reflecting the distribution of pseudocysts and fluid collections (Fig. 304-2D). The splenic artery is most frequently involved, followed by the inferior and superior pancreatic duodenal arteries. This diagnosis should be suspected in patients with pancreatitis who develop upper gastrointestinal bleeding without an obvious cause or in whom thin-cut CT scanning reveals a contrast-enhanced lesion within or adjacent to a suspected pseudocyst. Arteriography is necessary to confirm the diagnosis.
Pancreatic Ascites and Pancreatic Pleural Effusions
Pancreatic ascites is usually due to disruption of the main pancreatic duct, often by an internal fistula between the duct and the peritoneal cavity or a leaking pseudocyst (Chap. 43). This diagnosis is suggested in a patient with an elevated serum amylase level in whom the ascites fluid has both increased levels of albumin [>30 g/L (>3.0 g/dL)] and a markedly elevated level of amylase. The fluid in true pancreatic ascites usually has an amylase concentration of >20,000 U/L as a result of the ruptured duct or leaking pseudocyst. Lower amylase elevations may be found in the peritoneal fluid of patients with acute pancreatitis. In addition, ERCP often demonstrates passage of contrast material from a major pancreatic duct or a pseudocyst into the peritoneal cavity. As many as 15% of patients with pseudocysts have concurrent pancreatic ascites. The differential diagnosis should include intraperitoneal carcinomatosis, tuberculous peritonitis, constrictive pericarditis, and Budd-Chiari syndrome.
If the pancreatic duct disruption is posterior, an internal fistula may develop between the pancreatic duct and the pleural space, producing a pleural effusion, which is usually left-sided and often massive. This complication often requires thoracentesis or chest tube drainage.
Treatment usually requires the use of nasogastric suction and parenteral alimentation to decrease pancreatic secretion. In addition, paracentesis is performed to keep the peritoneal cavity free of fluid and, it is hoped, to effect sealing of the leak. The long-acting somatostatin analogue octreotide, which inhibits pancreatic secretion, is useful in cases of pancreatic ascites and pleural effusion. If ascites continues to recur after 2 to 3 weeks of medical management, the patient should be operated on after pancreatography to define the anatomy of the abnormal duct. A disrupted main pancreatic duct can also be treated effectively by stenting. Patients in whom ERCP identifies two or more sites of extravasation are unlikely to respond to conservative management and/or stenting.
Chronic Pancreatitis and Pancreatic Exocrine Insufficiency
General and Etiologic Considerations
Chronic inflammatory disease of the pancreas may present as episodes of acute inflammation in a previously injured pancreas or as chronic damage with persistent pain or malabsorption. The causes of relapsing chronic pancreatitis are similar to those of acute pancreatitis (Table 304-1), except that there is an appreciable incidence of cases of undetermined origin. In addition, the pancreatitis associated with gallstones is predominantly acute or relapsing-acute in nature. A cholecystectomy is almost always performed in patients after the first or second attack of gallstone-associated pancreatitis. Patients with chronic pancreatitis may present with persistent abdominal pain, with or without steatorrhea; some (~15%) present with steatorrhea and no pain.
Patients with chronic pancreatitis in whom there is extensive destruction of the pancreas (less than 10% of exocrine function remaining) have steatorrhea and azotorrhea. Among American adults, alcoholism is the most common cause of clinically apparent pancreatic exocrine insufficiency, while cystic fibrosis is the most frequent cause in children. In up to 25% of American adults with chronic pancreatitis, the cause is not known; that is, they have idiopathic chronic pancreatitis. Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been documented in patients with idiopathic chronic pancreatitis. It has been estimated that in patients with idiopathic pancreatitis the frequency of a single CFTR mutation is 11 times the expected frequency and the frequency of two mutant alleles is 80 times the expected frequency. The results of sweat chloride testing are not diagnostic of cystic fibrosis in these patients. However, these patients have functional evidence of a defect in CFTR-mediated ion transport in nasal epithelium. It is suggested that up to 25% of patients with idiopathic chronic pancreatitis may have abnormalities of the CFTR gene. The therapeutic and prognostic implication of these findings remain to be determined. In other parts of the world, severe protein-calorie malnutrition is a common cause. Table 304-5 lists other causes of pancreatic exocrine insufficiency, but they are relatively uncommon.
The events that initiate an inflammatory process in the pancreas are still not well understood, and the many hypotheses will not be reviewed here. In the case of alcohol-induced pancreatitis, it has been suggested that the primary defect may be the precipitation of protein (inspissated enzymes) in the ducts. The resulting ductal obstruction could lead to duct dilation, diffuse atrophy of the acinar cells, fibrosis, and eventual calcification of some of the protein plugs. However, the fact that some alcoholic patients with recurrent acute pancreatitis show no evidence of chronic pancreatitis does not support this hypothesis. In fact, experimental and clinical observations have shown that alcohol has direct toxic effects on the pancreas. While patients with alcohol-induced pancreatitis generally consume large amounts of alcohol, some consume very little (50 g/d or less). Thus prolonged consumption of "socially acceptable" amounts of alcohol is compatible with the development of pancreatitis. In addition, the finding of extensive pancreatic fibrosis in patients who died during their first attack of clinical acute alcohol-induced pancreatitis supports the concept that such patients already have chronic pancreatitis.
Patients with relapsing chronic pancreatitis may present with symptoms identical to those of acute pancreatitis, but pain may be continuous, intermittent, or absent. The pathogenesis of this pain is poorly understood. Although the classic description is of epigastric pain radiating through the back, the pain pattern is often atypical; the pain may be worst in the right or left upper quadrant of the back or may be diffuse throughout the upper abdomen; it may even be referred to the anterior chest or flank. Characteristically it is persistent, deep-seated, and unresponsive to antacids. It often is worsened by ingestion of alcohol or a heavy meal (especially one rich in fat). Often the pain is severe enough to necessitate the frequent use of narcotics.
Weight loss, abnormal stools, and other signs or symptoms suggestive of malabsorption (see Table 286-5) are common in chronic pancreatitis. However, clinically apparent deficiencies of fat-soluble vitamins are surprisingly rare. The physical findings in these patients are usually not impressive, so that there is a disparity between the severity of the abdominal pain and the physical signs (other than some abdominal tenderness and mild temperature elevation).
In contrast to relapsing acute pancreatitis, the serum amylase and lipase levels are usually not elevated in chronic pancreatitis. Elevations of serum bilirubin and alkaline phosphatase levels may indicate cholestasis secondary to chronic inflammation around the common bile duct (Fig. 304-3). Many patients demonstrate impaired glucose tolerance, and some have an elevated fasting blood glucose level.
The classic triad of pancreatic calcification, steatorrhea, and diabetes mellitus usually establishes the diagnosis of chronic pancreatitis and exocrine pancreatic insufficiency but is found in less than one-third of chronic pancreatitis patients. Accordingly, it is often necessary to perform an intubation test such as the secretin stimulation test, which usually gives abnormal results when 60% or more of pancreatic exocrine function has been lost. Approximately 40% of patients with chronic pancreatitis have cobalamin (vitamin B12) malabsorption, which can be corrected by the administration of oral pancreatic enzymes. There is usually a marked excretion of fecal fat (Chap. 286), which can be reduced by the administration of oral pancreatic enzymes. The serum trypsinogen (Chap. 303) and the D-xylose urinary excretion test are useful in patients with "pancreatic steatorrhea," since the trypsinogen level will be abnormal, and D-xylose excretion usually is normal. A decreased serum trypsinogen level strongly suggests severe pancreatic exocrine insufficiency.
The radiographic hallmark of chronic pancreatitis is the presence of scattered calcification throughout the pancreas (Fig. 304-3). Diffuse pancreatic calcification indicates that significant damage has occurred and obviates the need for a secretin test. While alcohol is by far the most common cause, pancreatic calcification also may be seen in cases of severe protein-calorie malnutrition, hereditary pancreatitis, posttraumatic pancreatitis, hyperparathyroidism, islet cell tumors, and idiopathic chronic pancreatitis. A large prospective study has shown convincingly that pancreatic calcification decreases or even disappears spontaneously in one-third of patients with severe chronic pancreatitis; this outcome may also follow ductal decompression. Pancreatic calcification is a dynamic process that is incompletely understood.
Sonography, CT, and ERCP greatly aid the diagnosis of pancreatic disease. In addition to excluding pseudocysts and pancreatic cancer, sonography and CT may show calcification or dilated ducts associated with chronic pancreatitis (Fig. 304-4). ERCP is the only major technique that provides a direct view of the pancreatic duct. In patients with alcohol-induced pancreatitis, ERCP may reveal a pseudocyst missed by sonography or CT.
Complications of Chronic Pancreatitis
The complications of chronic pancreatitis are protean. Cobalamin (vitamin B12) malabsorption occurs in 40% of patients with alcohol-induced chronic pancreatitis and in virtually all with cystic fibrosis. It is consistently corrected by the administration of pancreatic enzymes (containing proteases). It may be due to excessive binding of cobalamin by cobalamin-binding proteins other than intrinsic factor, which ordinarily are destroyed by pancreatic proteases and therefore do not compete with intrinsic factor for cobalamin binding. Although most patients show impaired glucose tolerance, diabetic ketoacidosis and coma are uncommon. Similarly, end-organ damage (retinopathy, neuropathy, nephropathy) is also uncommon, and the appearance of these complications should raise the question of concomitant genetic diabetes mellitus. A nondiabetic retinopathy, peripheral in location and secondary to vitamin A and/or zinc deficiency, is common in these patients. Effusions containing high concentrations of amylase may occur into the pleural, pericardial, or peritoneal space. Gastrointestinal bleeding may occur from peptic ulceration, gastritis, a pseudocyst eroding into the duodenum, or ruptured varices secondary to splenic vein thrombosis due to inflammation of the tail of the pancreas. Icterus may occur, caused either by edema of the head of the pancreas, which compresses the common bile duct, or by chronic cholestasis secondary to a chronic inflammatory reaction around the intrapancreatic portion of the common bile duct (Fig. 304-3). The chronic obstruction may lead to cholangitis and ultimately to biliary cirrhosis. Subcutaneous fat necrosis may appear as tender red nodules on the lower extremities. Bone pain may be secondary to intramedullary fat necrosis. Inflammation of the large and small joints of the upper and lower extremities may occur. The incidence of pancreatic carcinoma is increased in patients with chronic pancreatitis who have been followed for 2 or more years. Twenty years after the diagnosis of chronic pancreatitis, the cumulative risk of pancreatic carcinoma is 4%. Perhaps the most common and troublesome complication is addiction to narcotics.
Therapy for patients with chronic pancreatitis is directed toward two major problems-pain and malabsorption. Patients with intermittent attacks of pain are treated essentially like those with acute pancreatitis (see above). Patients with severe and persistent pain should avoid alcohol completely and avoid large meals rich in fat. Since the pain is often severe enough to require frequent use of narcotics (and hence addiction), a number of surgical procedures have been developed for pain relief. ERCP allows the surgeon to plan the operative approach. If there is a stricture of the pancreatic duct, a local resection may ameliorate the pain. Unfortunately, isolated localized strictures are not common. In most patients with alcohol-induced disease, the pancreas is diffusely involved, and surgically correctible localized ductal disease is rare. When there is primary ductal obstruction and dilation, ductal decompression may provide effective pain palliation. Short-term pain relief may be achieved in up to 80% of patients, while long-term pain relief occurs in approximately 50%. In some of these patients, however, pain relief can be achieved only by resecting 50 to 95% of the gland. Although pain relief is achieved in three-quarters of these patients, they tend to develop pancreatic endocrine and exocrine insufficiency and must be treated with pancreatic enzyme replacement therapy. It is important to screen patients carefully, for such radical surgery is contraindicated in those who are severely depressed or suicidal or who continue to drink. Procedures such as splanchnicectomy, celiac ganglionectomy, and nerve blocks usually bring only temporary relief and are not recommended. Endoscopic treatment of chronic pancreatitis may involve sphincterotomy of the minor or major pancreatic sphincter, dilatation of strictures, removal of calculi, or stenting of the ventral or dorsal pancreatic duct. Although many of these techniques are technically impressive, none has been subjected to a randomized trial in patients with chronic pancreatitis. In addition, significant complications-acute pancreatitis, pancreatic abscess, damage to the pancreatic duct, and death-have occurred in up to 36% of patients after stent placement.
Three double-blind trials have demonstrated that administration of pancreatic enzymes decreases abdominal pain in selected patients with chronic pancreatitis. In these trials, approximately 75% of the patients evaluated experienced pain relief. The patients most likely to respond are those with mild to moderate exocrine pancreatic dysfunction, as evidenced by an abnormal secretin test, normal fat absorption, and minimal abnormalities on ERCP examination. These clinical observations seem to fit with data from human beings and experimental animals demonstrating a negative feedback regulation for pancreatic exocrine secretion controlled by the amount of proteases within the lumen of the proximal small intestine. It seems reasonable to use the following approach for patients with severe, persistent, or continuous abdominal pain thought to be caused by chronic pancreatitis. After other causes of abdominal pain (peptic ulcer, gallstones, etc.) have been excluded, a pancreatic sonogram should be done. If no mass is found, a secretin test may be performed, because its results usually are abnormal in cases of chronic pancreatitis with pain. If the results are abnormal (i.e., decreased bicarbonate concentration or volume output), a 3- to 4-week trial of pancreatic enzyme administration is appropriate. Eight conventional tablets or capsules are taken at meals and at bedtime. There are a number of studies suggesting that patients may have small-duct chronic pancreatitis and chronic abdominal pain with a normal appearance on radiographic evaluations (ultrasound, CT, ERCP) but abnormal results on hormone stimulation tests (secretin test) and/or abnormal pancreatic histology. Such minimal-change chronic pancreatitis may respond well to pancreatic enzyme therapy (non-enteric-coated) for relief of abdominal pain. If no relief is obtained, and especially if the volume secreted during the secretin test is very low, ERCP should be performed. If a pseudocyst or a localized ductal obstruction is found, surgery should be considered. A patient who has dilated ducts may be a candidate for a surgical ductal decompression procedure. This procedure provides short-term relief in up to 80% of patients, although long-term results are closer to 50%. Some studies have shown octreotide to be effective in decreasing abdominal pain in patients with severe large-duct disease. If no surgically remediable lesion is found and severe pain continues despite abstinence from alcohol, subtotal pancreatic resection may be necessary.
The treatment of malabsorption rests on the use of pancreatic enzyme replacement therapy. Diarrhea and steatorrhea are usually improved by this treatment, although the steatorrhea may not be completely corrected. The major problem is delivering enough active enzyme into the duodenum. Steatorrhea could be abolished if 10% of the normal amount of lipase could be delivered to the duodenum at the proper time. This concentration of lipase cannot be achieved with the current preparations of pancreatic enzymes, even if the latter are given in large doses. The reason for these poor results may be that lipase is inactivated by gastric acid, that food empties from the stomach faster than do the pancreatic enzymes, and that batches of commercially available pancreatic extracts vary in enzyme activity.
For the usual patient, two or three enteric-coated capsules or eight conventional (non-enteric-coated) tablets of a potent enzyme preparation should be administered with meals. Some patients using conventional tablets require adjuvant therapy to improve enzyme replacement treatment. H2 receptor antagonists, sodium bicarbonate, and proton pump inhibitors are effective adjuvants. Antacids containing calcium carbonate or magnesium hydroxide are not effective and may actually result in increased steatorrhea. Several publications have reported colonic strictures in patients with cystic fibrosis receiving extraordinarily high doses of high-potency pancreatic enzyme preparations. Such lesions have not been reported in adults with chronic pancreatitis.
Supportive measures include diet restriction and pain medications. The diet should be moderate in fat (30%), high in protein (24%), and low in carbohydrate (40%). Restriction of long-chain triglyceride intake can help patients who do not respond satisfactorily to pancreatic enzyme therapy. Use of foods containing mainly medium-chain fatty acids, which do not require lipase for digestion, may be beneficial. Nonnarcotic analgesics should be emphasized. Patients taking narcotic drugs for pain relief often become addicted and continue to have pain.
Patients with severe exocrine pancreatic insufficiency secondary to alcohol who continue to drink have a high mortality rate (in one series, 50% of patients who were followed for 5 to 12 years died during this period) and significant morbidity (weight loss, lassitude, vitamin deficiency, and narcotic addiction). Chronic pancreatitis carries significant medical and social costs. A recent study found that pancreatitis led to retirement in 11% of patients with the disease, accounting for 45% of all retirements. In 87% of patients with chronic pancreatitis unable to maintain gainful employment, alcoholism was a contributing factor. Patients with chronic pancreatitis also use substantial medical resources. In 1987 in the United States, this diagnosis accounted for 122,000 recorded outpatient visits and 56,000 hospital admissions. Pain may abate if progressive severe exocrine insufficiency continues. Patients who abstain from alcohol and use vigorous replacement therapy for maldigestion-malabsorption do reasonably well.
Hereditary pancreatitis is a rare disease that is similar to chronic pancreatitis except for an early age of onset and evidence of hereditary factors (involving an autosomal dominant gene with incomplete penetrance). A genome-wide search using genetic linkage analysis identified the hereditary pancreatitis gene on chromosome 7. An R117H mutation in the cationic trypsinogen gene occurs in most of the families with hereditary pancreatitis that have been studied. Molecular modeling predicts the formation of hydrolysis-resistant trypsin that could lead to pancreatic autodigestion. These patients have recurring attacks of severe abdominal pain which may last from a few days to a few weeks. The serum amylase and lipase levels may be elevated during acute attacks but usually are normal. Patients frequently develop pancreatic calcification, diabetes mellitus, and steatorrhea, and, in addition, they have an increased incidence of pancreatic carcinoma. Such patients often require ductal decompression for pain relief. Abdominal complaints in relatives of patients with hereditary pancreatitis should raise the question of pancreatic disease.
When the ventral pancreatic anlage fails to migrate correctly to make contact with the dorsal anlage, the result may be a ring of pancreatic tissue encircling the duodenum. Such an annular pancreas may cause intestinal obstruction in the neonate or the adult. Symptoms of postprandial fullness, epigastric pain, nausea, and vomiting may be present for years before the diagnosis is entertained. The radiographic findings are symmetric dilation of the proximal duodenum with bulging of the recesses on either side of the annular band, effacement but not destruction of the duodenal mucosa, accentuation of the findings in the right anterior oblique position, and lack of change on repeated examinations. The differential diagnosis should include duodenal webs, tumors of the pancreas or duodenum, postbulbar peptic ulcer, regional enteritis, and adhesions. Patients with annular pancreas have an increased incidence of pancreatitis and peptic ulcer. Because of these and other potential complications, the treatment is surgical even if the condition has been present for years. Retrocolic duodenojejunostomy is the procedure of choice, although some surgeons advocate Billroth II gastrectomy, gastroenterostomy, and vagotomy.
Pancreas divisum occurs when the embryologic ventral and dorsal pancreatic anlagen fail to fuse, so that pancreatic drainage is accomplished mainly through the accessory papilla. Pancreas divisum is the most common congenital anatomic variant of the human pancreas. Current evidence indicates that this anomaly does not predispose to the development of pancreatitis in the great majority of patients who harbor it. However, the combination of pancreas divisum and a small accessory orifice could result in dorsal duct obstruction. The challenge is to identify this subset of patients with dorsal duct pathology. Cannulation of the dorsal duct by ERCP is not as easily done as is cannulation of the ventral duct. Patients with pancreatitis and pancreas divisum demonstrated by ERCP should be treated with conservative measures. In many of these patients, pancreatitis is idiopathic and unrelated to the pancreas divisum. Endoscopic or surgical intervention is indicated only when the above methods fail. If marked dilation of the dorsal duct can be demonstrated, surgical ductal decompression should be performed. The appropriate therapy for patients without dilation of the dorsal duct is not yet defined. It should be stressed that the ERCP appearance of pancreas divisum-i.e., a small-caliber ventral duct with an arborizing pattern-may be mistaken as representing an obstructed main pancreatic duct secondary to a mass lesion.
In macroamylasemia, amylase circulates in the blood in a polymer form too large to be easily excreted by the kidney. Patients with this condition demonstrate an elevated serum amylase value, a low urinary amylase value, and a Cam/Ccr ratio of less than 1%. The presence of macroamylase can be documented by chromatography of the serum. The prevalence of macroamylasemia is 1.5% of the nonalcoholic general adult hospital population. Usually macroamylasemia is an incidental finding and is not related to disease of the pancreas or other organs.
Macrolipasemia has now been documented in a few patients with cirrhosis or non-Hodgkin's lymphoma. In these patients, the pancreas appeared normal on ultrasound and CT examination. Lipase was shown to be complexed with immunoglobulin A. Thus, the possibility of both macroamylasemia and macrolipasemia should be considered in patients with elevated blood levels of these enzymes.