A practical guide to pancreatitis

received his M.D. from Harvard Medical School Magna Cum Laude in 1963. At that time, he received the Good Physician Award of the Massachusetts Medical Society. After two years of surgical training at the Massachusetts General Hospital, he went to the Gastroenterology Section of the National Institute of Health in Bethesda, Maryland. There he did clinical and laboratory research on pancreatic insufficiency and biochemical aspects of gastrointestinal disorders; he then returned to the Massachusetts General Hospital to complete his surgical residency. Following a Fellowship in the Gastrointestinal Unit of the Massachusetts General Hospital, Dr. Warshaw joined the full-time surgical staff at that institution and simultaneously became an attending physician in the Gastrointestinal Unit. Since 1972, he has been actively involved in teaching of surgery and gastrointestinal diseases to undergraduates and to residents, and has lectured widely as a visiting professor and in multiple post-graduate programs. Throughout this time, he has continued to maintain an active program of clinical investigation and to run a laboratory involved with biochemical mechanisms of gastrointestinal diseases.

graduated from the University of Texas and Southwestern Medical School. He was trained in internal medicine and gastroenterology at the Massachusetts General Hospital. He has continued as a member of the staff of the Primary Care Program and Gastrointestinal Unit at the Massachusetts General Hospital. Dr. Richter’s special interests include clinical epidemiology and diagnostic strategies for pancreatic and biliary diseases.

LONG a neglected organ, lurking with relative invisibility in the retroperitoneum, the pancreas in the last decade has become a major focus of clinical interest as new techniques have enabled us to “see” and evaluate it. Computed tomography (CT), ultrasound scans (US), and endoscopic retrograde cholangiopancreatography (ERCP) in particular have provided us with the ability to study, noninvasively, the anatomical changes that characterize pancreatitis. Concomitantly many laboratories have been active in trying to elucidate the biochemical events and the markers of pancreatic inflammatory diseases. With these advances has come a veritable avalanche of books and articles on pancreatitis. We do not desire to duplicate these or to compile an encyclopedic analysis of the available literature. Rather, it is our intent to present a practical approach to pancreatitis, primarily a distillation of our experience at the Massachusetts General Hospital over the last 15 years. Several assumptions underlie our philosophy. First, pancreatitis is certainly not a single disease. The term encompasses a variety of local and systemic responses to a multiplicity of injuries, acute and chronic. It is highly probable that the diseases we call acute pancreatitis and chronic pancreatitis are entirely different processes, and that several distinct diseases exist within each of these headings. There is as yet no generally accepted classification of pancreatitis, including that set forth. at Marseilles in 1963, scheduled to be revised at a reconvening of the Marseilles conference in 1984. Table 1 depicts attempts at TABLE TYPE Clinical

Radiologic

Pathologic

Clinicalopathologic (Marseilles, 1963)

l.-CLASSIFICATIONS

OF PANCREATITIS

CATEGORIES Acute (edematous, fulminant) Acute recurrent Chronic: Painful Painless Acute: Phlegmonous Chronic: Calcific Acute: Edematous Hemorrhagic Necrotizing Chronic: Postnecrotic scarring Fibrotic Calcific Acute Acute relapsing Chronic relapsing Chronic

LIMITATIONS Cannot acute flares

in many cases distinguish pancreatitis from acute of chronic pancreatitis

Insensitive, misses mild or early cases of either acute or chronic pancreatitis Not

applicable to clinical questions because of unavailability of tissue cases

Acute relapsing cannot be distinguished from chronic relapsing in most cases

in most

classification based on clinical or pathologic factors, but all of them ignore the distinctions or interrelationships of the various separate diseases, and none provides clinically essential information. For practical purposes, it may be best simply to regard pancreatitis tentatively as either acute (first attack), recurrent acute (two or more attacks; patient apparently well between attacks), or chronic (persistent symptoms of pain, signs of diabetes, malabsorption, calcification, or characteristic changes on pancreatography). It is important to recognize that chronic pancreatitis may be entirely painless. Second, we can identify certain antecedent factors associated with pancreatitis, but we understand little of how these factors really initiate the disease, nor are we sure of the subsequent pathophysiological steps. This statement is as true of gallstone pancreatitis as it is of alcoholic pancreatitis. There is no experimental model of pancreatitis that is known to be equivalent to human pancreatitis in its induction, development, and histopathology. Third, as a consequence of not knowing what causes or propagates pancreatitis, we have no means at present to stop it. Especially in acute pancreatitis, we are dependent on endogenous control mechanisms to halt the disease, and fortunately they usually do control it. Our role as treating physicians is still largely limited to providing general supportive care, refraining from aggravating the disease process, identifying remediable antecedents, and otherwise directly treating only the complications. Whether we can intercept any form of pancreatitis and actually modify or alter the inflammation (as distinct from its complications) remains to be proved. ANTECEDENTS

OF PANCREATITIS

Table 2 lists factors that have been associated with pancreatitis. Note that many of these are unique to one or the other section, a fact which suggests that acute pancreatitis does not as a rule evolve into chronic pancreatitis. In gallstone pancreatitis, for example, the pancreas heals and reassumes its normal architecture even after repeated acute attacks, unless one of those attacks results in severe disruption and consequent scarring. Obstruction of the pancreatic duct from healing of a necrotizing injury or pseudocyst can lead to chronic obstructive injury in the pancreatic segment distal to the block,247 a phenomenon recently described as “upstream pancreatitis”.123 It has been hypothesized that gallstones passing through the ampulla of Vater can cause local scarring and stenosis of the bile duct and pancreatic duct and thereby lead to chronic pancreatitis, but this sequence of events has never been validated. Pancreas divisum, an anomaly in which the main pancreatic duct empties via the 8

TABLE

2.-ANTECEDENTSOFPANCREATITIS

ACUTEPANCREATITIS Mechanical block at ampulla Gallstones Ampullary stenosis Accessory papilla stenosis (pancreas divisum) Duodenal diverticulum Toxic and metabolic factors Alcohol (?) Hypertriglyceridemia (endogenous, exogenous) Hypercalcemia (hyperparathyroidism, exogenous) Drugs (definite: azathioprine, sulfonamides, thiazides, furosemide, estrogen contraceptives, tetracycline; probable: chlorthalidone, corticosteroids, ethacrynic acid, procainamide, L-asparginase) Post transplantation (renal) Infection Viruses (mumps, Coxsackie, adenovirus) Mycoplasma Worms (Ascaris, clonorchis) Trauma (External, operative, pancreatography) Ischemia Circulatory shock (cf. cardiac surgery) Vasculitis Emboli Hypothermia Malignant hypertension Neoplasms Primary pancreatic Metastatic to pancreas Pregnancy (Other than gallstones and hypertriglyceridemia) Other diseases Enteric duplication cysts Crohn’s disease of duodenum Penetrating peptic ulcer Cystic fibrosis of pancreas Acute intermittent porphyria Thrombotic thrombocytopenic purpura CHRONIC PANCREATITIS Alcohol Hypertriglyceridemia Hypercalcemia Hereditary Hemochromatosis Annular pancreas Biliary cirrhosis Sclerosing cholangitis Choledochal cyst Cystic fibrosis Nutritional (protein) deficiency Post scarring from acute pancreatitis

9

duct of Santorini and the accessory papilla, has been associated with recurrent acute pancreatitis,lg thought to be due to relative stenosis at the accessory papilla.263 The occasional association of pancreas divisum and true chronic pancreatitis raises the possibility that the obstructing lesion is at fault here also.263 If so, this might be an unique example of uncomplicated acute pancreatitis evolving to chronic pancreatitis because of chronic outlet obstruction. Intermittent flares of inflammation in patients with chronic pancreatitis may be indistinguishable from an attack of acute pancreatitis, and such patients may be free of any symptoms between attacks. Nonetheless, fibrosis, acinar and islet cell loss, and chronic inflammation are thou ht to precede the first clinical symptoms, perhaps by years.2 %2 In some cases, symptoms may never appear. Clinically, patients with chronic pancreatitis and intermittent acute symptoms may be indistinguishable from those with relapsing acute pancreatitis unless calcification, diabetes, or steatorrhea is already evident. ERCP may show the pancreatic duct changes of chronic pancreatitis.163 Such a list serves also to remind us that every instance of pancreatitis has a cause. We may not comprehend what it is, but it exists. “Idiopathic” is a traditional evasion for “agnogenic,” meaning “of unknown cause.” To the extent that we successfully whittle down the size of the “idiopathic” group, we are simultaneously building up our stock of potentially avoidable or remediable circumstances. Pancreas divisum, as noted, is an example of a cause which was not appreciated until a few years ago, but which can be treated surgically to prevent further attacks. Other categories dictate specific measures such as reduction of plasma triglycerides158 or avoidance of exposure to toxic drugs. The natural history of recurrent acute pancreatitis often can be altered by attending to a specific cause, but the course of chronic pancreatitis is less easily changed. Ischemia is worthy of special mention. Several recent studies have pointed out the susceptibility of the pancreas to ischemic injury, both experimental4 ’ 174 and clinical.260 A form of acute pancreatitis seemingly initiated by pancreatic infarction rather than by chemical or enzymatic injury has been reported in patients with vasculitis,lo4, 17i accidental hrpothermia,142 and particularly after open heart surgery.1g62 26 Moreover, the importance of this phenomenon extends beyond these areas because pancreatic necrosis can develop in any form of acute pancreatitis. The relative inadequacy of blood flow in the pancreatic microcirculation during acute pancreatitis seems to be a key factor in determining whether the attack will be mild and self-limited, or go on to pancreatic necrosis and its complications.

10

ACUTE

PANCREATITIS

PATHOPHYSIOLOGY The pancreas, one of the most active sites of protein synthesis in the human body, produces large quantities of proteolytic enzymes, including trypsin, chymotrypsin, and elastase. These exist normally in the pancreatic cells and secretions as inactive proenzymes and are activated only after contact with duodenal enterokinase. Activation of these enzymes is thought to be a key event in pancreatitis, not only by directly destroying tissues (including blood vessels) with which they come in contact, but also by activating a cascade of other enzymes such as phospholipase A (lecithinase) which propagate the damage in other directions. Nonetheless, activation of proteolytic enzymes, at least within the duct lumen, cannot be the sole prerequisite for initiating pancreatitis. After transduodenal sphincteroplasty or pancreaticojejunal anastomoses, reflux of enterokinase-rich intestinal contents into the pancreatic duct necessarily results in activation of trypsin within the pancreatic duct system but does not cause pancreatitis. Similarly, hypersecretion alone is unlikely to cause trouble. Despite the occasional case of acute pancreatitis appearing after a gastronomic binge, experimental models have shown that it is quite difficult to produce pancreatitis from hypersecretion alone.lr7 Since Opie’s classic description of pancreatitis resulting from a gallstone impacted in the ampulla,17’ obstruction of the pancreatic duct has been accepted as a cause of pancreatitis. Obstruction alone, however, may be insufficient: if the pancreatic duct is ligated outright, the result is usually atrophy of exocrine tissue, not pancreatitis, as Banting and Best showed when by this method they proved persistence of the islets of Langerhans 60 years ago. Although the initiating step is unknown, it is widely accepted that a crucial early step in acute pancreatitis involves loss of integrity of the duct system, allowin escape of activated enfi zymes into the pancreatic tissue.17322o The immediate local effects on the pancreas are inflammation, edema, and ischemia. Contributions to the latter include reduction of regional blood flOW,227 local maldistribution of flow within the pancreas207 loss of plasma volume from the capillaries and consequent sludging, and vascular plugging by thrombi thou&t to be the result of disseminated intravascular coagulation. Presumably the tissue damage would be potentiated by the actions of escaped proteolytic enzymes. The ischemic and enzymatic injuries can combine to produce both local and widespread regional necrosis. Free fatty acids generated from circulating triglycerides by local lipolysis may contribute to the pancreatic injury in patients with 11

hypertriglyceridemia.200 Experimental evidence from the isolated perfused pancreas model suggests that the generation of oxygen-derived free radicals may magnify the endothelial lesion.201 In addition to the local effects on the pancreas, there is exudation into the surrounding tissues andgeritoneal cavity of a fluid rich in activated enzymes,156’ 16’, 2 histamine-releasing factors,168 vasoactive amines including kallikrein and bradykironin, n% 228 and unidentified other evil humors which have found effects on myocardial function,64S ‘lo vascular tone,43, 6P endothelial integrity,77, 229 and complement activation.is2 The number and nature of active agents are largely unknown, but they are presumed in general to be the mediators of many systemic manifestations of pancreatitis. Once released from the pancreas, they reach the circulation by absorption into the bloodstream from the peritoneal cavity,265 or perhaps by way of the lymphatic drainage. 173The murky brown pool of toxic ascitic fluid available for absorption may be as much as 10 L. Why most pancreatitis is relatively mild and self-limited, and why some goes on to cause major regional destruction of the pancreas and its surroundings, is poorly understood. One can postulate that the stimulus may be greater or more persistent in some cases, that the ability of the gland to react may be variable (certainly there is less functional pancreatic parenchyma in chronic pancreatitis), or, perhaps most important, that the endogenous control mechanisms may be more or less adequate to the task. Little is known of these controls, but antiproteases such as al-antitrypsin and a2-macroglobulin appear to be of importance. The former binds trypsin, inactivates it, and serves as a carrier to transfer it to the latter. Complexes of a2-macroglobulin with proteases are cleared by the reticuloendothelial system.156 Exhaustion of this mechanism is thought to be associated with uncontrolled and complicated pancreatitis,73 1527156 whereas enhancement of the system appears to confer protection7 Prostaglandins also may be involved in cytoprotection of pancreas cells during pancreatitis.59 CLINICAL PRESENTATION Pancreatitis begins with local inflammation of the pancreas, but has the potential for widespread manifestations affecting almost any organ system. The typical presentation is of upper abdominal pain, often with radiation through to the back. Nausea, vomiting, and low-grade fever usually accompany the pain. Tenderness is most often limited to the upper abdomen and is not usually accompanied by rebound tenderness or other signs of peritonitis. Occasionally the pain and tenderness may be generalized, and there may be enough irritating exudate in the peritoneal cavity to produce impressive peritoneal signs simulating 12

a perforated ulcer, infarcted or perforated bowel, or acute appendicitis (when the exudate trickles down the mesenteric root into the right lower quadrant). Rarely a patient has no pain but presents with distention, ileus, fever, and tachycardia; this form of the disease is particularly associated wit$grimary ischemic necrosis as seen after open heart operation or accidental hypothermia.14’ A very rare patient may present only with peripheral manifestations such as subcutaneous fat necrosis or pancreatic arthritis. Mild pancreatitis is usually limited to the local abdominal manifestations just described and will subside within 1-3 days. In more severe cases, the cardiovascular system is the next most likely to be involved. Tachycardia, loss of circulating plasma volume, and hypotension are the characteristic changes. These are due to the combined effects of (1) pathologic capillary endothelial permeability, allowing body-wide leak of intravascular fluid into third spaces,77’ 22g (2) relative myocardial depression despite increased cardiac outputJ5”’ 64, ‘lo and (3) decreased peripheral vascular resistance. 3S5 ’ 64 The resulting shock state may not respond to intravenous (IV) volume replacement, no matter how vigorous, and is the major cause of death in the first week of acute pancreatitis. Respiratory insufficiency is also quite common. Asymptomatic hypoxemia, perhaps due to increased right-to-left shunting, has been demonstrated in 50%-70% of patients with acute pancreatitis.58, lo7, ls4, ls7 Hypoxemia may occur insidiously within the first day or two without radiographic changesis heralded only by increasing tachypnea, or may proTess to florid pulmonary edema, usually after 3-4 days (Fig 1). 5g The mechanism of the early asymptomatic hypoxemia is not known, but symptomatic respiratory insufficiency and pulmonar edema have been attributed to an alveolar-capillary leak.25 B Proposed agents of the Fig 1 .-Pancreatitis lung, an alveolar-capillary leak syndrome caused by endothelial membrane injury and leading to noncardiogenic pulmonary edema. At left is the normal chest radiograph of a 24-year-old man on admission; at right is the appearance of the lungs 3 days later.

alveolar membrane injury include either circulating proteolytic enzymes 34 or vasoactive amines,167, 168922g the action of hospholipase A on pulmonary membranes and surfactant,237’ 2!2 or the harmful effects of circulating free fatty acids47’ ii5 (which are greatly increased in those patients with associated hypertriglyceridemia and pancreatitis).52 Nonspecific compromise of respiratory function can be magnified by elevation of the diaphragm, atelectasis, pulmonary infiltrates, and pleural effusions associated with the subdiaphragmatic inflammatory process.165 Respiratory failure is more likely to occur in the sickest patients. Its contribution to the mortality of acute pancreatitis has been estimated to be about 30%.184S 187 The need for intubation and ventilator{ support is a predictor of a 75% likelihood of a fatal outcome.’ ’ Renal failure in pancreatitis is due in part to hypovolemia.20S 26, g2 However, renal function mar deteriorate without oliguria or any period of hypotension,sg, 2 and it may not respond to volume replacement. There is evidence to suggest that the injury is mediated by circulating vasoactive substances that cause intrarenal vasoconstriction and increased renal vascular resistance with reduced glomerular filtration.270 Histologic studies have shown deposits of fibrin in the glomeruli,g5, “’ possibly the result of activation of the coagulation mechanism by trypsin.216 Fat necrosis occurs often in omental and retroperitoneal fat, presumably due to local release of lipase and vascular compromise. It also is seen occasionally in subcutaneous tissues, particularl on the extremities,175 and infrequently in synovial tislesions sue, ’ ;Y5 bone,220 and pericardium.175 The extra-abdominal produce respectively subcutaneous red nodules (Fig 2), peripheral arthritis, bone pain, and pericarditis. The relationship of these lesions to circulating lipases has not been clear inasmuch as concomitant serum levels of lipase have frequently been norma1,236 and the lesions can be reproduced experimentally by IV infusion of the toxic ascites.22g It is possible that so-called pancreatic encephalopathy is a related phenomenon, caused by focal demyelination. High lipase levels have been reported in the cerebrospinal fluid of such patients7’ and IV administration of lipase in experimental animals causes focal demyelination.23g Subcutaneous fat necrosis alone is not necessarily associated with a worse pro nosis, but when multiple sites are involved, mortality is high. B75 Hyperglycemia is common but usually of little clinical significance. It is most often the product of markedly elevated plasma levels of glucagon,72, 218 rather than of true insulin deficiency. Insulin levels are in fact either elevated7’ or only slightly decreased.218 It is uncommon to have sufficient destruction of islet cells to produce significant or lasting insulin deficiency. The hy14

Fig 2.-Patches tizing pancreatitis.

of subcutaneous fat necrosis on the leg of a patient The affected areas are indurated and erythematous.

with

necro-

perglycemia is transitory and tends to subside within a few days as glucagon levels return to normal. The hypocalcemia of pancreatitis almost never reaches levels sufficient to cause tetany or cardiac conduction problems. Very low calcium levels (< 7 mg/dl) are usually associated with a but rarely produce recognizable symptoms. The grave attack”’ fall in serum calcium is popularly but probably incorrectly attributed to local formation of calcium soaps in extravascular sites of lipolysis and fat necrosis.75 The total calcium se uestered in extravascular soaps is only a paltry 1 or 2 gm. 75’ 226 Although much of the apparent fall may simply be related to decreased serum albumin levels, and therefore not of physiologic importance,lo5 ionized calcium levels decrease as well.’ ’ lg3 The mechanism may be related in part to inadequate parathyroid hormone secretion154 or function,lo6’ lg3 or to lowered serum magnesium levels.15 It is probably not due to elevated levels of calcitonin.267 New evidence suggests that calcium flux may be more important than calcium levels9 with calcium moving into certain tissues, including muscle, liver, and pancreas.33 LABORATORY DIAGNOSIS OF ACUTE PANCREATITIS There is no reliable test for pancreatitis. A number of them are useful, but clinical assessment is still the final means of constructing the diagnostic picture. Serum Amylase The serum amylase level is still the single most useful test. In most cases of uncomplicated pancreatitis, the serum amylase 15

level rises within 2-12 hours of the onset of symptoms and returns to normal over the next 3-5 days.‘, 5o Persistent elevation of the serum amylase level after 10 days usually implies a complication, such as pseudocyst or abscess. Early resolution of hyperamylasemia may indicate early resolution of the pancreatitis, but pancreatic necrosis may develop despite a normal serum amylase level, and even severe hemorrhagic pancreatitis may be associated with a normal level,2, 271 perhaps because of extensive destruction of the gland.” 27 There is no correlation between the serum amylase elevation and the etiology, prognosis, or severity of the disease.2’ ‘, lo8 The serum amylase level may be artifactually normal in as many as lo%-30% of persons with acute pancreatitis, especially2S 279271 in alcoholics with underlying chronic pancreatitis21g or patients with elevated serum lipid levels (triin the glycerides > 500 mg/d1).547 132 Occult hyperamylasemia presence of hypertriglyceridemia can be “unmasked” by performing serial dilutions of whole serum, measuring the amylase activity in the diluted serum, and multi 1 ing by the dilution factor to obtain the true amylase value. 13!?, %6 The presumed inhibitor of amylase is present only during the first few days of acute 54asncreatitis and is not a persistent property of lipemic serum. Interpreting the combination of abdominal pain, hyperlipemia, and normal serum amylase levels may be further confounded by the fact that patients with hyperlipemia may have crises of abdominal pain with no clinical or laboratory evidence of pancreatic inflammation.15* Many nonpancreatic diseases may be associated with hyperamylasemia (Table 3). Among these, disorders with accompanying abdominal pain pose a particularly difficult differential diagnostic problem. For example, stones in the common bile duct may produce chemical derangements and a clinical syndrome TABLE

8.--NONPANCREATIC

CAUSES

OF HYPEFAMYLASEMIA

Renal disease: Acute and chronic renal failure Salivary gland disease: Mumps, parotitis, sialadenitis, maxillofacial surgery, other trauma Liver disease: Cirrhosis, fulminant hepatitis, trauma Gastrointestinal disorders: Common bile duct stones, acute cholecystitis, penetrating peptic ulcer, intestinal obstruction, afferent loop syndrome, acute appendicitis, Crohn’s disease, mesenteric infarction Metabolic dysfunction: Diabetic ketoacidosis, nonspecific postoperative changes Neoplastic disease: Lung (primary and metastatic), pancreas, parotids, colon, ovary Gynecologic disorders: Ruptured ectopic pregnancy, ruptured graafian follicle, ovarian neoplasms and cysts, salpingitis, endometritis Intracranial pathology: Cerebral trauma Macroamylasemia “Normal” hyperamylasemia 16

virtually identical to acute pancreatitis.131 Presumably in that circumstance there is a mechanical block to excretion of pancreatic amylase, resulting in the rise of the serum levels of the enzyme along with SGOT and other biliary enzymes, a “pseuAlthough peptic ulcer disease is considered one dopancreatitis.” of the causes of acute pancreatitis, gastric or duodenal ulcer with;s;t2 ancreatitis may be associated with hyperamylasemia, ’ 5! perhaps reflecting increased absorption of amylase across the defective mucosal surface. When there is perforation of the ulcer, elevation of the serum amylase level is probably the result of absorption of amylase-rich gastric and duodenal contents from the peritoneal cavity.“* Intestinal obstruction without evidence of pancreatitis may be associated with hyperamylasemia.51’ 250 The rise in serum amylase is probably the result of luminal amylase leaking through the compromised intestinal wall. The afferent loop syndrome is a similar phenomenon in which intestinal obstruction is added to the factor of abnormally hi h pressure against which the pancreatic duct must empty. 17%;Other intra-abdominal diseases associated with hyperamylasemia include acute appendicitis51 Crohn’s disease,250 ruptured aortic aneurysm, aortic dissection, and mesenteric infarction.250 True pancreatitis, perhaps on an ischemic basis, may occur in several of these conditions. Hyperamylasemia following abdominal surgery-most commonly biliary surgery and gastroduodenal surgery-in many cases is due to genuine pancreatitis, presumably the result of trauma to the pancreas. In many cases, however, postoperative hyperamylasemia is nonpancreatic in ori@tg7716o and may reflect poorly understood metabolic changes. Macroamylasemia Persistent unexplained hyperamylasemia in a patient with normal renal function may be the result of macroamylasemia, a term that was coined to describe circulating amylase complexed with a macromolecule.31 Too large to be filtered through the glomerulus, this complex accumulates in the blood. The urine amylase value is either low or normal, and the am lase clearance rate is characteristically well below normal.313 Y37, 250 Macroamylasemia may also be present when the serum amylase level is normal, although this circumstance is uncommon.25 Macroamylasemia occurs in 0.4% of the general ropulation25 and in 5.9% of patients with hyperamylasemia.‘* It may be present transiently during acute illness, but more commonly it persists for months to years3” ‘*’ More than 60% of patients with macroamylasemia have associated abdominal pain,253 the cause and significance of which are not known. The main importance of identifying this phenomenon rests in avoiding unnecessary testing and treatment for nonexistent pancreatic disease. 17

Renal Clearance

of Amylase

Renal clearance of amylase compared with creatinine clearance (amylase-creatinine clearance ratio, ACCR) increases to a mean value about three times normal in 90% of patients with acute pancreatitis.137’ 250 The ACCR does not rise in chronic pancreatitis (except during an acute relapse), pancreatic cancer, or in association with chronic pancreatic pseudocysts. The ACCR may be helpful in distinguishing between acute pancreatitis and other causes of hyperamylasemia. Warshaw and Fuller confirmed elevation of the ratio in 39 of 42 patients with acute pancreatitis and found that it was normal in 44 patients with hyperamylasemia due to other causes.25o The ACCR separates patients with common duct stones and chemical hyperamylasemia (“pseudopancreatitis”) from those with true pancreatitis secondary to the stones.131 Similarly, patients with hyperamylasemia associated with peptic ulcers of the duodenum or stomach usually do not have true pancreatitis, and they have a normal ACCR despite the hyperamylasemia.258 Because the ACCR is elevated in patients with renal failure2” 137 and in occasional patients with intra-abdominal conditions other than pancreatitis, the value of the ACCR has been questioned. Its major value is probably not in diagnosing pancreatitis, but in helping to exclude it.240 Since the ACCR rises so reliably in acute pancreatitis,“’ 250 a normal ACCR despite hyperamylasemia may be taken as good evidence against acute pancreatitis.240 Amylase

Isoenzyme Analysis

Separation of amylase into its isoenzyme fractions by various biochemical techniques offers considerable increase in specificity over measurement of the total serum amylase, although the cumbersome and expensive techniques involved have thus far limited their widespread clinical application. Two principal isoamylases have been identified: pancreatic type and salivary type, named for their physicochemical similarity to amylase derived from organ extracts of pancreas and salivary glands.254 Representative electrophoretic patterns of the serum isoamylases in various diseases associated with hyperamylasemia are shown in Figure 3. Amylase isoenzyme analysis is more specific than the total serum value in detecting acute pancreatiamylase tis. 32, “‘3 12i, 1307241,266 Studies of patients at high risk for the development of pancreatitis, including those with normal serum amylase levels, have shown the serum isoamylase to be particularly sensitive in detecting the presence of pancreatitis. It is also valuable in directing attention away from the pancreas when the increased amylase in the serum is shown to be of nonpancreatic origin. In two prospective series of patients with presumed pancreatitis, 25%-28% had hyperamylasemia of extra18

B

A

“’

NORMAL

SERUM

0.8

ACUTE PANCREAT,TfS 4

ACOTESALPtNGf77S

0.1 -

FRACTION-NUMBER

FRACUON

NUMBER

Fig 3.-A, separation of amylase isoenzymes in normal human serum, pancreatic secretions, and saliva by polyacrylamide gel electrophoresis. The major pancreatic and salivary isoamylases are easily identifiable in serum. B, electrophoresis of serum amylases in some diseases associated with hyperamylasemia. The isoamylases differ from normal in unique and characteristic patterns.‘54 (Reproduced by permission from J. Surg. Res. 22:362, t977.)

pancreatic origin.izO~ 266 In most cases, however, the diagnosis of pancreatitis is self-evident. Isoenzyme analysis should probably be limited to patients with persistent hyperamylasemia of more obscure etiology or to those who have multiple possible sources of serum amylase elevationz4> 32si30s136 A substance derived from wheat protein has been found to inhibit human salivary am&l”;:; to a significantly greater degree If most of the serum amylase acthan pancreatic amylase. ’ tivity is blocked in the presence of the wheat inhibitor, the origin of the amylase is not the pancreas. Differential amylase inhibition can therefore be used as a poor man’s simple version of isoamylase determination.i2’ It is now available in a commercial kit, and although the limits of its specificity have not yet been explored, it is among the most promising developments in the diagnosis of pancreatitis. Other Serum Tests Serum levels of Zipase and amylase tend to parallel one another, but lipase is more specific than amylase for pancreatic disease.28T 250 Given the recent development of rapid accurate lipase assays, the serum lipase may yet become a prime test for the diagnosis and differential diagnosis of Eancreatitis. Trypsin is found only in the pancreas. Accurate measurement of serum trypsin has been precluded by the ubiquitous presence of trypsin inhibitors in the serum. The development of a radioimmunoassay for trypsin now makes it possible to mea19

sure serum levels, called trypsin-like immunoreactivity (TLI). High levels of TLI have been found in all cases of acute pancreatitis studied.76, 15%223 Elevations of the alkaline phosphatase, transaminase, and bilirubin levels may occur during pancreatitis and suggest biliary obstruction.131 Extrahepatic obstruction in this setting could be due to the presence of a common duct stone or to compression of the lower end of bile duct by the swollen pancreas. These tests do not, therefore, distinguish between cholelithiasis with secondary pancreatitis and acute pancreatitis of other pathogenesis. 13’ The tests are not useful for the diagnosis of pancreatitis, but are helpful for evaluating one of its associated features, common duct obstruction. LABORATORY

INDICES

OF

THE SEVERITY

OF

PANCREATITIS

In addition to the variety of tests available for the diagnosis of acute pancreatitis, attempts have been made to identify those patients at high risk for late complications. Ranson’s System For this purpose Ranson et al. have identified a group of clinical and laboratory signs to be gathered over the first 48 hours of hospitalization (Table 4).ls3 In general, the greater the number of positive signs, the greater the probability of death.“’ This system has been particularly valuable for stratifying groups of patients for truer comparison of the effects of therapy. In part because its components require 48 hours for assessment and in part because they were derived from an analysis based on the statistical chance of dying, these prognostic signs seem less applicable to immediate therapeutic decisions.‘i It is also a misuse to apply the system at a later time to the assessment of patients with specific secondary events such as pancreatic abscesses. TABLE

4.-RANSON’S SIGNS PANCREATITIS

OF SEVERE

ACUTE

At admission: Age > 55 years Blood glucose > 200 mgidl Serum lactic dehydrogenase > 300 IUiL SGOT > 250 units White blood count > 16,000/mm3 At 48 hours after admission: Hematocrit fall > 10% Blood urea nitrogen rise > 5 mg/dl Serum calcium < 8 mgidl Arterial PO, < 60 mm Hg Base deficit > 4 mEq/L Estimated fluid sequestration > 6,000 ml 20

RNase Isoenzyme Warshaw and Lee255 demonstrated that in some patients with pancreatitis, the value of a serum ribonuclease (RNase) isoenzyme associated with the pancreas rose within a few days of the onset of pancreatitis and remained elevated. The finding correlated well with the occurrence of pancreatic necrosis in those patients. In contrast, patients with an uncomplicated clinical course, including those with severe early pancreatitis, had normal values. In animal experiments this type of ribonuclease is released in lar e quantities from anoxic pancreas, but not from other organs.24 5 Elevations of serum RNase levels do+ however, occur in renal failure and in certain malignancies. Our continuing experience suggests that serum RNase levels may be useful in monitoring patients with pancreatitis in order to detect those with irreversible pancreatic injury who require surgical debridement before the necrotic tissue becomes infected. Methemalbumin Levels Methemalbumin in serum and in ascitic fluid has been touted as a means of differentiating hemorrhagic from edematous pancreatitis.‘14 Although elevated serum levels may be detected as early as 12 hours into the course of hemorrhagic pancreatitis, similar elevations occur in ruptured ectopic pregnancy, intestinal ischemia, and intestinal obstruction,i6 conditions also associated with hyperamylasemia. The significant false positive rate in patients with abdominal catastrophes other than hemorrhagic pancreatitis renders this test of limited value. Peritoneal Aspiration or Lavage Attempts have been made to demonstrate the presence of pancreatitis or predict the severity of the disease by early peritoneal aspiration or lavage. At present most investigators agree that the amylase concentration in the peritoneal fluid is of no diagnostic significance.24, 45, 153,235 Other conditions, including strangulated or infarcted small bowel, g eritonitis, 235 perforated peptic ulcers, and high intestinal fistulas ’ may be associated with elevated peritoneal fluid amylase values, and patients with ancreatitis may have normal peritoneal fluid amylase levels. 2B The physical properties of the fluid have been scrutinized in the effort to predict the severity of an attack. McMahon et a1.153 devised a color chart for this purpose in which a severe attack was heralded by dark peritoneal fluid. The ability to aspirate more than 10 ml of free fluid, regardless of color, was also considered indicative of a severe attack. Although these criteria were superior to clinical impression alone, at least in the first 24 hours, the group of criteria derived by Ranson et a1.1s3 are at least as accurate, and less invasive. Whether evaluation of the peritoneal fluid can accurately select those patients who will benefit from therapeutic peritoneal lavage has not been established. 21

The presence of bacteria in the lavage fluid has been claimed by some investigators to indicate a surgical lesion rather than pancreatitis.45 There have been false positive results, and needless laparotomy has been performed based on this assumption.24 Peritoneal aspiration does not seem to have a role in the management of acute pancreatitis at present. Laparotomy Since none of the laboratory criteria for the diagnosis of acute pancreatitis are without error, exploratory laparotomy remains necessary on occasion when the diagnosis is in doubt. Laparotomy should be reserved for patients whose conditions progressively deteriorate despite appropriate supportive treatment, those with marked peritonitis, and those whose laboratory findings are atypical for pancreatitis. Since an exploratory laparotomy does not increase the mortality from acute pancreatitis,234 the dangers of missing a diagnosis of surgically correctable visceral compromise far outweigh the risk of “unnecessary” laparotomy. RADIOGRAPHIC

TESTS

FOR PANCREATITIS

No radiographic technique is a sensitive index of acute pancreatitis, but some techniques have an important role in confirming the clinical impression of pancreatitis, especially when the serum amylase level is normal. Radiographic tests assist in excluding other causes of acute abdominal pain and aid in the early detection of complications. The plain film of the abdomen and the upper gastrointestinal (GI) tract series have been largely superseded by abdominal ultrasound and CT. Ultrasound Ultrasound has been used in cases of suspected acute pancreatitis to provide further evidence of the presence of pancreatic inflammation and to detect gallstones, especially when there is no history of antecedent alcohol abuse. The examination of the pancreas is abnormal in 30%-50% of patients with acute pancreatitis, i2& i51* 214 but the major limitation of the test is that the pancreas cannot be adequately visualized in 25%-50% of patients, because intra-abdominal gas or excess body fat obscures tissue planes.214 Since ultrasound can detect cysts as small as 2 cm, it is the method of choice for the identification and serial examination of pseudocysts or pancreatic abscess (Fig 4).74 By distinguishing between true cysts and solid inflammatory masses (phlegmon), ultrasound makes it possible to avoid unnecessary laparotomy, to time optimal surgical drainage of pseudocysts as well as to detect their resolution,g0 and to alert the surgeon to the presence of multiple cysts. It is also valuable in defining peripancreatic fluid collections and to aid in sampling them for bacterial culture. 22

Fig 4.-Ultrasound scan of the left upper quadrant vere pancreatitis. The lucent area (arrow) represents docyst), but the associated necrotic pancreas and evident.

7 days after me onset of sea fluid collection (acute pseuretroperitoneal tissues are not

Computerized Tomography CT offers the advantages of better visualization of retroperitoneal structures and better overall visualization of the pancreas. The examination is more accurate, regardless of the presence of abdominal gas or the patient’s size or clinical status.155, ‘14 The changes detected by CT reflect pancreatic inflammation and edema in approximately 70% of proven cases. The CT scan is even more useful in diagnosing later complications of acute pancreatitis such as pancreatic necrosis, gseudocyst, abscess, or peripancreatic fluid collections126* 213,2147’ 2; in providing a baseline for serial examinations when technical difficulties preclude the use of ultrasound; and in demonstrating the extent of inflammatory changes beyond the pancreas.” The CT scan can also be used to guide needle aspiration of peripancreatic fluid collections to obtain samples for bacterial culture.272 Endoscopic Retrograde Cholangiopancreatography The risk of provoking or exacerbating pancreatitis during the acute phase of illness has limited the role of ERCP in the diagnosis of acute pancreatitis. Later in the course of uncomplicated edematous pancreatitis, when the inflammation has subsided, the pancreatogram is usually normal. After more severe pancreatitis, ERCP may reveal residual postinflammatory than es including ectatic, irregular duct anatomy, focal strictures, 12 B ,241 and areas of proximal duct dilation. ERCP has little place in establishing whether or not pancreatitis is present since that can usually be accomplished by other means. Its role is in determining whether there is preexisting or residual structural abnormality of the pancreas, such as pan23

creatic cancer, pancreas divisum, ampullary stenosis, pancreatic duct stenosis, choledochal cysts,l** or choledocholithiasis. The search for these abnormalities is best deferred until the acute illness has thoroughly subsided. Transhepatic Cholangiography There has been little published experience with the application of transhepatic cholangiography in acute pancreatitis. Coppa and colleagues6i used it to confirm the diagnosis of gallstone pancreatitis, to distinguish gallstone pancreatitis from alcoholic pancreatitis, and to confirm the necessity for surgical treatment of the underlying biliary tract disease. In their small series, the test was safe, gave information clearly superior to that available from any other source, and saved some patients the risk of a needless laparotomy. Biliary Excretion Scans Radionuclide biliary excretion scans (HIDA, DICIDA, PIPIDA, etc.) have been used to try to differentiate intraluminal obstruction of the bile duct by a stone from extrinsic compression by the swollen pancreas: in other words, to distinguish between biliary and alcoholic pancreatitis. Evidence to date suggests that this test is inadequate to the task.

MEDICAL TREATMENT OF ACUTE PANCREATITIS Effective Therapy Many measures have been tried in an effort to modify the natural course of the disease. Of these, only fasting the patient appears to make an undisputed difference, since premature feeding will commonly cause reactivation of the inflammation and is said to increase the chance of developing a pancreatic abscess.ls5 Most cases of acute pancreatitis are self-limited and subside spontaneously. In about 90%, the endogenous control mechanisms are successful, and the physician must take care only to stay out of the way. During this period, maintenance of adequate circulation and tissue perfusion requires vigorous IV volume replacement and monitoring of the vital signs, urine output, and often central venous pressure. In critically ill patients, measurements of cardiac output and pulmonary wedge pressure with a Swan-Ganz catheter are necessary. Arterial blood gases should be followed at least every 12 hours for the first 3 days in patients with moderately severe pancreatitis, especially if the plasma triglyceride levels are increased.25g Supplemental oxygen should be provided if the arterial PO, declines. Whether albumin solutions are helpful (by replacing lost protein and better supporting the circulation) or harmful (by drowning the lung) is a matter of emotional and still unresolved dispute. Plasma may have a theoretical advantage over plain albumin solutions by providing protease inhibitors.7’ 15’

24

Probably Effective Therapy The rationale for using nasogastric suction is to “put the pancreas at rest” by reducing stimulation from antral distention and acid-induced secretion of secretin. Because studies of patients with milderzancreatitis do not show any benefit from nasogastric suction,i 4, 16’ it has become somewhat fashionable to decry it. Nonetheless, some patients clearly have recurrent inflammation when nasogastric suction is discontinued, and all patients with pancreatitis are at risk of vomiting and aspirating because of ileus. It is safer to use a tube. Cimetidine in theory might confer some of the same benefits as nasogastric suction. In practice, studies have shown it to be ineffective.48, 157 It (or antacids) will still be helpful in guarding against the hemorrhagic gastritis (stress ulceration) to which sick patients are susceptible, and for that reason we use it. Ineffective or Unproved Therapy Antibiotics have never been shown to be effective in preventing the later septic complications of acute pancreatitis, and their use may even promote selection of organisms more difficult to treat, including Candida.lgl Controlled trials in alcoholic pancreatitis of mild to moderate severit have shown no benefit from ampicillin or cephalosporins.82’ ’ B3 Advocates of antibiotics correctly point out that those trials are too restrictive in their scope and do not prove that more powerful drugs would not be of greater use in sicker patients or in gallstone pancreatitis. The question remains moot. It seems reasonable not to use antibiotics in mild to moderate alcoholic pancreatitis, but in gallstone pancreatitis or in fulminant cases, in which tissue necrosis is more likely and bacteria can be recovered from peripancreatic fluid early in the course,252 preemptive treatment with broadspectrum antibiotics can be justified in the hope of limiting bacterial invasion in this period of vulnerability. Hypocalcemia rarely reaches symptomatic levels. It is not only unnecessary to treat the calcium value, but it is usually futile. The magnitude of calcium flux and mobilization already occurring renders administered calcium inconsequential.g, 33 It is also unnecessary and even unwise to attempt rigid control of blood glucose by giving insulin. The hyperglycemia is due primarily to high glucagon levels7’, 218 and may fall rapidly as the disease subsides. Blood glucose levels of 200-300 mg/dl are acceptable. Intravenous hyperalimentation (TPN) is not necessary unless the course of the disease is protracted. Its early use may be poorly tolerated because of hyperglycemia. Trials have failed to show effectiveness of any of the following agents: anticholiner ics,56 Trasylol (aprotinin, a proteolytic enzyme inhibitor),62, 235 or glucagon (to reduce pancreatic secretion).62, 170 Still under investigation are inhibitors of ghospholipase A,237 prostaglandins,37* 5gF144 somatostatin,211’ 38 secre25

tin,lgO inhibitors of protein synthesis,145T lg8 scavengers of oxygen-derived free radicals201 protease-binding proteins,152 and stimulants of the reticuloendothelial system.7 Because of evidence that ischemic injury to the pancreas in acute pancreatitis is a major factor in the development of pancreatic necrosis,24g’ 255,260 there has been considerable interest in attem ts to protect and enhance the pancreatic microcirculation.6 SP ’ 7o Animal experiments have shown the effectiveness of sympathetic blockade,g1 heparin,27g and low molecular weight dextran.71 The latter is being evaluated in clinical trials. Corticosteroid drugs, which may in some cases cause pancreatitis,222 have also been evaluated in the treatment of the disease.l16 The results have been equivocal at best; beneficial effects may be due to enhancement of pancreatic blood flo~.~~~ OPERATIVE TREATMENT FOR ACUTE PANCREATITIS With support from modern techniques of anesthesia, intensive care, and blood banking, operation on the patient with acute pancreatitis can be performed safely,234 but its necessity is a matter of debate. In the century since Fitz’s description of the faces of severe pancreatitis, concepts of what operation can accomplish for the disease have waxed and waned, with the pendulum starting at cholecystostomy and pancreatic drainage, moving to total abstinence from surgery, and then swinging as far as emergency total pancreatectomy. Much of this confusion is now being resolved as the results have been evaluated, and especially as appropriate goals of intervention have been defined more clearly. Diagnostic Uncertainty As we have seen, there is still no foolproof diagnostic test for acute pancreatitis. While most patients presenting with upper abdominal pain and hyperamylasemia have pancreatitis, a similar presentation may be seen in patients with acute cholecystitis, penetrating and perforated peptic ulcers, strangulated or perforated bowel, mesenteric ischemia, intestinal obstruction, common duct stones, hepatitis, and diabetic ketoacidosis-all in the absence of pancreatitis. Even in this age of increasingly sophisticated diagnostic technology, it may be impossible to be sure, especially if the signs of peritoneal irritation are more prominent than is usual for pancreatitis. Laparotomy will in some cases be the safest means to establish the diagnosis with certainty and to avoid missing another disease in desperate need of surgical attention. It should not be a source of embarrassment to find acute pancreatitis when exploring an acute abdomen. When pancreatitis is found unexpectedly at laparotomy, there is an opportunity to deal with possible biliary pathology. The surgeon’s ability to palpate gallstones accurately may be im26

paired because of inflammation and distortion of the structures in the right upper quadrant. Stones are easily missed, perhaps in as many as 30% of proved cases. If there is doubt, an operative cholangiogram will be helpful. Cholecystectomy and common duct drainage are preferable if stones are found, but cholecystostomy may be safer in the presence of marked inflammation. Extended instrumentation of the common duct is unwise. Other than specific treatment of gallstones, no other surgical intervention is indicated for mild to moderate pancreatitis found unexpectedly. Routine cholecystostomy, peripancreatic drainage, and placement of lavage catheters are of no use.252 Early Intervention to Modify the Course of Pancreatitis Attempts to ameliorate the severity of acute pancreatitis and to prevent later complications may address either underlying pathogenetic factors or the pancreatic inflammation itself. GALLSTONE-INDUCED PANCREATITIS.-&XOmpreSSing the biliary tract and indirectly the pancreatic duct by cholecystostomy or choledochostomy was often used in the past for all kinds of acute pancreatitis but was never shown to be effective. With the demonstration that gallstones can be recovered from stools of most patients with gallstone-related pancreatitis3’ ‘I2 the importance of gallbladder stones passing into the common bile duct and thence obstructing or traumatizing the pancreatic duct orifice has been reemphasized. Acosta and his colleagues have reported from studies of Argentinians with gallstone pancreatitis that 63% will have stones impacted at the ampulla during the first 48 hours.*’ 5 Arguing that the longer a stone is allowed to obstruct the ampulla, the more likely is the pancreatitis to progress and become severe, they advocated the immediate removal of the obstructing stone to abort the progression of pancreatitis. In their series, removal of the impacted stones during the first 48 hours of the attack by common duct exploration and, if necessary, transduodenal sphincteroplasty seemed to reduce mortality from 16% to 2%. Others have not accepted these views. Percutaneous transhepatic cholangiography in patients with gallstone pancreatitis easily demonstrates the presence of common duct stones, but these are rarely impacted.61 Ransoni’l found that operating on 22 patients with gallstone pancreatitis during the first week of the attack led to a 23% mortality (three of four patients operated on within the first 48 hours died), while there were no deaths among 58 patients who were treated nonoperatively until the pancreatitis subsided and who later underwent elective cholecystectomy and common duct exploration. Similarly, Kelly,ii3 in a study of 172 patients, found impacted stones in 63% of patients operated on within 72 hours, but there was a 12% operative mortality in those patients. In contrast, when the operation was 27

delayed 5-7 days, only 5% still had impacted stones, and the operative mortality was nil. The pancreatitis in 15% of his patients did not subside but progressed and forced earlier surgical treatment. Transduodenal sphincteroplasty in the presence of acute pancreatitis has an appreciable risk of causing an abscess or duodenal fistula. 268 Experience with common bile duct decompression by percutaneous transhepatic tube placement or by endoscopic sphincterotomy is still too scant to know whether either of these techniques will be effective but safer than immediate surgical choledochotomy in gallstone pancreatitis. In Europe, endoscopic sphincterotomy is being used within increasing frequency igg and may well become the preferred first intervention. With the exceptions noted above, there is a consensus that the gallbladder should be removed and the bile duct cleared of stones after the pancreatitis has subsided, if possible. It was common to wait 4-6 weeks for the pancreatitis to heal thoroughly, but studies consistently show that 24%-48% of patients will have a recurrence of pancreatitis within that waiting period. ‘i3, “‘, 268 Consequently most surgeons, including ourselves, now prefer to perform the biliary tract operation during the same hospital admission, generally waitin g,L’7, days or until signs of pancreatic inflammation have gone. ’ The approach has the additional advantage of providing the time and opportunity to prove the presence of gallstones by repeated ultrasound examination or by cholangiography if the ultrasound study on admission was not conclusive. The ultrasound or CT scan can also be used to evaluate the subsidence of pancreatic edema before the decision is made to operate. PANCREATIC DRAINAGE AND DEFUNCTIONING.-II1 1970, Lawson and his colleagues at the Massachusetts General Hospital repopularized the concept of an operation designed to drain the pancreatic bed and reduce stimulation of the gland.lz4 The elements of their operation included placement of sump drains in the lesser sac next to the pancreas, a cholecystostomy tube or common bile duct drainage tube to decompress the biliary tree, a gastrostomy tube for prolonged gastric drainage, and a jejunostomy tube to allow postoperative enteral feeding without causing release of secretagogue hormones from the duodenum. Subsequently, Warshaw et al., analyzing the cumulative experience from this institution,252 found that approximately 5% of patients admitted with acute pancreatitis had been selected to receive the “triple-tube drainage.” The operation did not appear to help patients with relatively mild pancreatitis. The only patients in whom the tubes and drains appeared to change the course of the pancreatitis itself were those who were judged to be dying after 24-48 hours of maximal fluid resuscitation and 28

supportive care. These patients were characterized by continuing massive requirements for IV volume replacement (average, 3 L of colloid in the first 24 hours), hypotension, tachycardia, and oliguria, and they tended to develop respiratory failure and profound hypocalcemia. Whereas the predicted mortality for such patients was estimated to be more than 90%, nine of eleven patients clearly improved and seven ultimately survived. Two early responders died weeks later of sepsis. The success of this operation was thought to be due primarily to removal of the “toxic ascites,” the pancreatic exudate containing vasoactive substances discussed previously. The same objective can often be attained by percutaneous peritoneal lavage, which will be discussed below. The incidence of pancreatic or peripancreatic abscesses in patients undergoing sur.&a&triple-tube drainage for severe pancreatitis is 20%-40%. ’ While the high infection rate may be a natural consequence of pancreatitis, Ranson et al. have argued that the surgical procedure introduces bacteria into the susceptible area and increases the likelihood of infection.ls3 Because of this concern and the success of percutaneous peritoneal lavage therapy, the triple-tube operation as a primary therapeutic approach is used much less frequently now. The tube drainage of the biliary tract and stomach and the jejunal feeding tube (which obviates use of central venous catheters for nutrition in patients at high risk of sepsis) do have real value for some patients and should be considered if laparotomy is otherwise indicated. Although the tubes may risk complicating fistulas from the enterotomy sites,i4* this has not been a problem universally.252 We have found the tubes useful and continue to employ them in indicated circumstances. PANCREATIC RESECTION.-Because there is no known pharmacologic means to stop the progress of pancreatitis and because severe pancreatitis often leads to regional necrosis of large areas of the pancreas and peripancreatic fat (Fig 51, attempts have been made to gain control of fulminant pancreatitis by removing much io21 1’S or even all of the gland.13 Reports of this approach, principally from Europe, have shown that major left-sided (distal or subtotal) pancreatic resection can be accomplished with a mortality of under 40%.102, “* Pancreaticoduodenectomy or total pancreatectomy raises the mortality to 60% or more.13 Advocates of pancreatic resection in pancreatitis have thus far failed to define the criteria for selecting patients for operation. There are no proved clinical or laboratory indices for anticipating pancreatic necrosis, just “clinical judgment.” Moreover, the decision to operate is just the first problem. The surgeon must then decide which part of the pancreas to resect and how much to resect. Those decisions can be very difficult, both because surface changes may greatly misrepresent the degree of central 29

30

pancreatic injuryi” and because several days are required before the changes of pancreatic devitalization become visible. In the first few days, there is only massive swelling, with or without hemorrhagic staining. Because there has been no improvement in survival of patients treated by preemptive early pancreatic, resection compared to those treated by later debridement of clearly demarcated dead tissue, the latter timing and approach remain preferable. OPERATIVE TREATMENT FOR COMPLICATIONS OF ACUTE PANCREATITI~ Whereas the ability of anticipatory operative intervention to alter the course of the primary pancreatic inflammatory process remains doubtful, the role of reactive surgery in managing the complications of pancreatitis is much clearer. Each of those complications occurs at a consistent and predictable time and in a logical progression, and each requires an appropriate response. Early Phase (First 4 Days) This is the period of acute reversible effects of pancreatitis on diverse organ functions. All of these events, however immediately life-threatening, can subside without leaving lasting tissue injury. Severely affected patients will have an astounding loss of plasma volume, not just into the inflamed pancreas but into interstitial spaces all over the body as a result of increased capfor IV reillary permeability.77’ 22g The resultant requirements placement may be 3,000-5,000 ml of plasma (or correspondingly greater volumes of crystalloid solutions) per 24 hours.2 2 In spite of adequate replacement, estimated with the aid of central venous or Swan-Ganz catheters, patients may remain hypotensive and tachycardic, probably due to loss of peripheral vascular tone. Acute renal failure, oliguric or nonoliguric, is frequent even when the circulating plasma volume has been adequately maintained. Respiratory failure is due to a combination of rightto-left shunting, injury to alveolar membranes, and the effects of subdiaphragmatic inflammation. It typically develops insidiously1;sn2ighe second or third day and may then become rampant. 7 Many of the systemic effects of pancreatitis are believed to be mediated by circulating substances, particularly kinins and Fig 5.-Total necrosis of the pancreas. A, appearance at laparotomy of total pancreatic necrosis (7 days after onset of pancreatitis). The patient had been stable until day 5, when he developed a high fever and marked hypocalcemia. B, central pancreatic necrosis, not apparent until the thickened capsule was incised. The patient had persistent pain but no fever or leukocytosis. This operation was performed 1 month after the beginning of symptoms. CT scan showed central liquefaction within the pancreas. C, necrotic pancreas and peripancreatic fat debrided 8 days after onset of pancreatitis. The patient had persistent fever and tachycardia. 31

other vasoactive amines such as kallikrein and bradykinin, 167,16*, “* which can be found in the dark brown intraperitoneal exudate that is characteristically present in fulminant pancreatitis. 77 Its volume may rang e up to 10 L in the peritoneal cavity. In animal experimentslg5 and in clinical studies of human pancreatitis, as yet largely uncontrolled but nonetheless impressive, removal of the toxic ascites by p~riltsofi~s~l lavage leads to rapid and dramatic improvement. ’ ’ Within hours of the institution of lavage, most patients have a clear reduction of intravascular plasma loss, a return toward normal of blood pressure and pulse rate, and an improvement in respiratory exchange. These benefits are not seen with hemodialysis2’ a fact that underscores that lavage treatment cleanses the peritoneal cavity and prevents systemic absorption of toxic substances, but does not extract these substances from the bloodstream by dialysis. The indications for peritoneal lavage are still not well defined. It is certainly unnecessary and confers no benefit in pancreatitis of mild to moderate severity. It is also of no use in treating signs of inflammation persisting or developing after the first few days. The cause of late inflammation is more likely to be pancreatic necrosislzseudocyst, or abscess, none of which will be helped by lavage. Ranson has suggested using the criterion of three or more of his prognostic signs’*‘, 187 to select patients for treatment. In our view, lavage probably is properly applied to those patients who have evidence of major plasma volume loss, hypotension, tachycardia over 140 beats per minute, and whose condition does not stabilize but continues to deteriorate despite aggressive fluid therapy. How long the preliminary resuscitation efforts should be continued before lavage is undertaken may vary, but preferably is less than 24 hours. Peritoneal lavage to remove toxic ascites can be accomplished with the same technique and fluids used for renal dialysis. Some add antibiotics to the dialysate,“” M, 224 but the value of this tactic is unproved. Abdominal distention, high diaphragms, and incipient respiratory failure may mandate using smaller lavage volumes (1 L instead of 2), and lavage may precipitate the need for endotracheal intubation and assisted ventilation in such a patient. The lavage fluid need not be left in the peritoneal cavity to equilibrate, as it would be for dialysis, but can be evacuated immediately. The lavage therapy need be continued only until the systemic circulatory effects of the pancreatitis have abated, usually within 24-48 hours. Critically ill patients may subsequently require further dialysis for acute renal failure. The response to peritoneal lavage should be rapid and unequivocal. If improvement of circulatory function does not occur within a few hours, laparotomy may be needed. The remediable causes of failure of peritoneal lavage include the following: (1) an error in diagnosis-the patient may have a 32

perforated viscus or ischemic bowel rather than pancreatitis; (2) biliary sepsis-pancreatitis caused by common duct stone may also be associated with acute bacterial cholangitis that requires biliary decompression and drainage; (3) loculation of toxic ascites in the lesser peritoneal sac-if the foramen of Winslow is not widely patent, the pancreatic exudate may collect in the space behind the stomach where it is not readily accessible to the anterior percutaneous lavage catheter. Precise surgical placement of lavage catheters into the lesser sac will dispel this problem. Peritoneal lavage is not a treatment of the pancreatitis itself, but a treatment of its early-phase systemic effects mediated by circulating toxins. Successful control of the systemic effects by lavage does not alter the progression of the pancreatic injury or prevent the intermediate or late-phase developments of pancreatic necrosis and abscess.lil’ 186, 52 It has been estimated that 50% of patients in whom the early phase is severe enough to warrant peritoneal lavage will develop a pancreatic abscess. The mortality from the late complications nearly equals that of the early-phase shock from which these patients were rescued,l@ leading some to the nihilistic view that early death from shock has simply been exchanged for later death from sepsis. A more pragmatic response is that, having learned to keep most patients alive through the early phase, we must now improve our methods of treating the subsequent complications. Middle Phase (Days 4 to 15) It is only after several days of acute pancreatitis that irreversible tissue destruction becomes recognizable. Phlegmon or swelling of the pancreas, apparent on ultrasound or CT scans in 30%50% of patients214 and palpable in 15%-20%,242 represents edema and inflammation for the most part, but areas of necrosis may also develop. Infarction of the pancreas and peripancreatic tissues may occur in well-defined smaller geographic patchF:d in large segments such as the distal two thirds of the gland, or even in the entire pancreas (see Fig 5,A), with extensions far out into the retroperitoneum and mesenteries. The mechanisms of this regional injury appear to involve ischemia, due both to decreased regional blood flow and to poor local tissue perfusion, and subsequent potentiation by extravasated pancreatic enzymes that have been activated. If the necrotic areas are small, natural repair processes may be successful in healing them. Necrotic tissues that are not cleared may later become infected or may declare their presence by increasing signs of inflammation (fever, tenderness, loss of intravascular volume), often without hyperamylasemia. CT scans may show irregular lucent areas in the phlegmon suggestive of liquefaction necrosis (Fig 6). This finding is extremely helpful when present, and in our view indicates the need for debridement of the dead tissues before they 33

Fig 6.-Central necrosis of the pancreas. CT scan shows irregular central areas (arrows) that corresponded with necrotic pancreatic tissue debrided sequent operation.

lucent at sub-

become infected. We also perform needle aspiration of liquified areas to sample for the presence of bacteria, which would intensify the mandate for debridement. In some cases, areas of edema may simulate areas of necrosis before the latter develop a pseudocapsule. Based on our observations that ribonuclease is released when pancreatic cells die24g and that elevated serum RNase levels were consistently seen in patients with pancreatic necrosis,255 we are studying the use of serum RNase levels to monitor for pancreatic necrosis even in asymptomatic patients (Fig 7), in the hope of improving the criteria for early debridement. This test is invalidated by renal dysfunction and is not yet available in most other institutions. At present we recommend exploration if the CT scan shows a clear-cut major area of liquefaction, particularly if the patient has even minor signs of inflammation (low-grade fever, pain, leukocytosis, or hyperamylasemia). The operation consists first of examining the entire pancreas and surrounding region. Areas of blackened necrosis are usually obvious, but incision of the inflamed thickened peritoneum and surface of the gland may reveal unexpected areas of dead tissue within (see Fig 5,B). Conversely, the central core of the pancreas may be intact despite surface destruction.128 The debridement entails combined blunt and sharp dissection through planes that are largely bloodless because the local vessels have thrombosed. Finger diss&tion is particularly helpful in delineating pockets and extensions of cavities. The removed tissues consist of partly liquefied stringy mush (see Fig 5,C). Sufficient soft sump or closed-suction drains are left in the cavity to allow egress for both the pancreatic juice 34

leaking from the remaining pancreas and for additional dead tissues that demarcate and slough later. Bloody ooze may be controlled by additional stuffed Penrose drains which are used as packing and can be removed in several days. The suction drains often must remain in place for weeks or months, as long as fluid and detritus continue to exit. The reported postoperative mortality of 20%-40%102’ ii8 is caused mainly by sepsis and hemorrhage from eroded blood vessels in and around the operative site. In our own series, there has not been a death in the last 16 patients treated by debridement. Late endocrine and exocrine insufficiency are surprisingly exceptional even after exFig 7.-A, release of ribonuclease (RNase) from rat pancreas during 24 hours of anoxic incubation. Very little amylase is liberated by comparison.“49 (Reprinted by permission from Surgery 9.5537, 1984.) B, raised levels of RNase in the serum of patients with acute necrotizing pancreatitis. The patient represented by open circles had manifestations of shock in the first few days but responded to peritoneal lavage and had no further complications. The patient represented by closed circles developed persistent fever and a palpable mass which subsided spontaneously. The patient represented by triangles required debridement and drainage of necrotic pancreatic tissues.255 (Reprinted by permission from Surgev 86:227, 1979.)

35

tensive debridement, probably because much of the removed tissue is peripancreatic fat rather than pancreas. Pseudocysts arising after acute pancreatitis are usually the result of pancreatic necrosis and escape of activated pancreatic secretions. This type of pseudocyst, occurring as a part of the ongoing necrotizing process, is much more dangerous than seudocysts found in patients with chronic pancreatitis.63’ i* l? Although some acute pseudocgsts may be resorbed spontaneously if the pancreatitis subsides or may eventually become encapsulated and inactive, like chronic pseudocysts, many others will be found in unstable patients who are still sick and toxic during this middle phase of necrotizing pancreatitis. Scans may show the fluid collection (see Fig 4) but tend to underestimate the associated pancreatic and peripancreatic regional necrosis. Therefore, it remains preferable to drain the collection by an open operation, which allows removal of any necrotic tissues, rather than by percutaneous needle or catheter techniques, which do not. Continuation of the necrotizing pancreatitis, hemorrhage from the operative site, and sepsis combine to produce at least a 10% death rate from acute pseudocysts, in contrast to a figure close to 1% after drainage or chronic pseudocysts. The true hemorrhage associated with fulminant pancreatitis occurs during this middle stage and is caused by erosion of major blood vessels by elastase and other proteolytic enzymes. The initial lesions are pseudoaneurysms, found when the vessel wall is injured (Fig 8). If rupture occurs, life-threatening hemorrhage follows. Control of bleeding is urgently required to prevent exsanguination. Although control of bleeding can be accomplished by surgical exploration and ligation, the mortality from Fig &-Arterial days afler onset. are pseudoaneurysms

36

injury in acute pancreatitis-pancreatic angiogram obtained 9 The multiple small saccular dilatations of the pancreatic arteries caused by enzymatic digestion of the arterial wall.

this complication appears to be significantly reduced if the bleeding point is identified angiographically (Fig 9) and occluded by embolization.221 Usually operative debridement of the necrotic tissues will still be necessary but can be more safely and effectively accomplished after the bleeding has been controlled. Five of our last ten patients treated in this fashion have survived, a real improvement over our previous record. The major blood vessels passing through or near the pancreas-the colic branches of the superior mesenteric artery, the splenic artery, and gastroduodenal artery-are at risk of thrombosis. The resulting ischemia of bowel segments served by the arteries-particularly the proximal and transverse colon and duodenum-can be manifested by GI bleeding from sloughed mucosa,i full-thickness bowel infarction (Fig lo), enteric fistulas,147 or later strictures.143 The value of angiography in the detection of thrombosed visceral vessels in such a patient is not established. If infarcted bowel is found, the involved segment must be resected. It is safer under these circumstances to bring out both ends of the remaining bowel as stomas,147 rather than risk breakdown of an anastomosis. When the duodenum perforates, a pancreaticoduodenectomy may be necessary, but limited resection of the compromised duodenal wall and reconstruction with intraluminal decompression by tube drainage is preferable when possible.255 Gastric emptying may be impaired for long periods, even exceeding 6 weeks, due to mechanical compression of the gastric outlet and duodenum by pancreatic swelling and to duodenal Fig 9.-Embolization of bleeding ruptured artery. Celiac angiogram in a 74-yearold woman who suffered a massive intra-abdominal hemorrhage 8 days after the start of pancreatitis. There is extravasation of contrast medium from a branch of the gastroduodenal artery (arrow). The bleeding point was occluded by transcatheter embolization, and the patient survived.

Fig IO.-Infarction of the colon in pancreatitis. examination, performed 14 days after the onset been passed per rectum at 10 days, and severe peared 4 days later. There is barium leaking from colon (black arrow) and barium lying free beneath

Appearance on barium enema of pancreatitis. Fresh blood had left-sided abdominal pain had apthe infarcted splenic flexure of the the diaphragm (white arrow).

atony. On occasion, a gastrojejunostomy may be necessary to relieve the obstruction and to permit resumption of oral feeding. Compression of the intrapancreatic portion of the common bile duct by the acutely edematous pancreas (Fig 11) is common, causing obstructive jaundice with serum bilirubin levels that often reach 3-4 mg/dl and even up to 8 mg/d1.44,131 Nonetheless, it is almost never necessary to decompress the bile duct operativelyr31, I48 except to remove common duct stones or relieve bacterial cholangitis.252 The narrowed segment of common bile duct will resume its normal configuration when the pancreatitis subsides. Late Phase (After 15 Days) The new development most likelzto appear after the second Abscesses arise from secweek of pancreatitis is an abscess. ondary infection of necrotic pancreatic and peripancreatic tissues, the usual organisms being enteric gram-negative rods, often in combination. Candida on occasion may be the predominant agent,lgl especially in patients who have received antibiotics. The overall incidence of pancreatic abscess after acute pancreatitis is 4%, but there is a positive correlation with the severity of the original pancreatitis. “6 243 Of patients requiring peritoneal lavage or exploration in the earl ;$f will go on to develop pancreatic abscess. 186,&2;z;;;e;; gested that too early feeding (before 11 days) of patients who have had severe pancreatitis promotes pancreatic abscesses.ls5 Any patient who is still febrile or who develops a fever 2 or more weeks after the onset of pancreatitis must be presumed to be developing an abscess until proved otherwise. A mass is pal38

Fig Il.-Obstruction of the common duct in pancreatitis. Cholangiogram shows persistent (1 month) obstruction of the lower common bile duct due to compression by the swollen pancreas in a 67-year-old woman with acute pancreatitis originally triggered by gallstones.

pable in the minority, and even leukocytosis and fever are not obligatory features. Ultrasound and CT scans have become the best means of diagnosing pancreatic abscesses. The CT appearance may be indistinguishable from that of sterile liquefaction necrosis of the pancreas (see Fig 6) unless gas bubbles are present in the abscess (Fig 12). Pancreatic abscesses that manifest relatively early, especially in the patient who never became asymptomatic, are likely to contain activated enzymes associated with ongoing necrosis.205 They carry extra morbidity and mortality because of the uncontrolled destructive process. Abscesses that manifest later (3-5 weeks after onset), often with a symptom-free interval of apparent well-being, tend to be simpler collections of pus, the residual of the attack, and behave similarly to other types of intra-abdominal abscess. The imperative of treatment is adequate drainage. Without it mortality is virtually 1OO%.243 In an extremely rare patient the abscess may drain spontaneously into the stomach or duodenum and the patient survives, although major hemorrhage usually accompanies this event. Antibiotics alone have never cured a 39

Fig 12.-CT scan of a pancreatic abscess. The obvious gas bubbles within the pancreas and in the left perirenal space are considered pathognomonic of infection.

pancreatic abscess. Attempts to drain pancreatic abscesses by nonsurgical percutaneous catheter techniques (using CT guidance) have been only moderately successful (60%) in comparison with such drainage for other forms of intra-abdominal abscess.87 The failure of this approach may be due to the associated necrotic tissue and continuing pancreatic inflammation, which require the more complete debridement and larger drains used at laparotomy. The preferred surgical approach is by laparotomy, which allows full evaluation of the pancreas and its surroundings, as well as adequate exposure to control points of hemorrhage that may be encountered unexpectedly. Thirty percent of patients will have multiple abscesses, and these may erode widely through the retroperitoneum, out into the bowel mesenteries, up into the mediastinum or pleural spaces, or down into the genitalia (Fig 13). Aggressive, wide, and complete drainage is mandatory. An astounding degree of tissue necrosis and purulent fluid can hide behind a seemingly innocuous area of induration. These must be incised, explored, and drained. Extrapolating from this position, Bradley and Fulenwider have had a small but successful experience with open packing of major pancreatic abscesses associated with ongoing necrotizing pancreatitis.42 Reoperation for further drainage of additional abscesses may be needed in one third of patients. Percutaneous catheter drainage of these recurrent abscesses is an attractive alternative to multiple reoperations in some difficult circumstances. The reported mortality nonetheless ranges up to 40%.243 Over the last 10 years the incidence of death from pancreatic abscesses in our series has fallen from 38% (10/26, 1974-19781, to 5% (l/19, 1979-1984). We believe these improved results are due in large measure to 40

Fig IL-Pancreatic abscess right side of the scrotum. This eroded down the retroperitoneum by permission from Surg. C/in.

which has necessitated and drained through the abscess, originating in the head of the pancreas, and out through the inguinal canaL2“* (Reprinted North Am. 54:621, 1974.)

greater use of CT and ultrasound scanning, and more aggressive surgical drainage.

earlier

diagnosis,

Persisting Pancreatitis An occasional patient continues to have low-grade signs of pancreatic inflammation for many weeks or even several months, with no focal areas of pathology demonstrable by CT scan to target for debridement or drainage. ERCP may identify irreversible injury to the pancreatic duct (Fig 141, or underlying Fig 14.-Endoscopic pancreatogram showing a foreshortened cut off at the neck of the gland by a necrotizing injury.

duct

of Wirsung,

Fig 15.-Cholangiopancreatogram obtained via the cystic duct in an 18-year-old girl with recurrent acute pancreatitis. There is filling of an enteric duplication cyst which is presumed to be the cause of the pancreatitis. She was successfully treated by resection of the head of the pancreas (Whipple procedure).

anomalies (Fig 15) that do not allow the pancreatitis to subside. In other cases there may be microabscesses or unrecognized duodenal wall injury. Resection of the pertinent area, even if it requires pancreaticoduodenectomy, however radical that may seem, may be the only option available. We have resorted to pancreaticoduodenectomy for acute pancreatitis four times in Fig 16.--Retrograde cholangiopancreatogram in a patient with pancreatitis. Both the bile duct and the pancreatic duct were.dilated empty after 30 minutes. These findings indicate ampullary stenosis, cured by transduodenal sphincteroplasty.

42

recurrent acute and failed to The patient was

the last 4 years. The operation was performed at times ranging from 7 to 12 weeks after the onset of the attack. All four patients left the hospital within 2-4 weeks. INTERVAL EVALUATION AFTER ACUTE PANCREATITIS Once the patient has recovered from acute pancreatitis, it is time to look for remediable causes to prevent recurrence. Other than information to be obtained from the history (drugs, etc.), the pertinent investigations during this interval include assessFig 17.-Endoscopic retrograde pancreatography in pancreas divisum. A, typical study of the duct of Wirsung obtained by cannulating the major papilla. The duct is foreshortened but does not end abruptly. It arborizes only within the pancreatic head. The remainder of the duct system cannot be seen. B, pancreatogram obtained by cannulating the accessory papilla. The duct of Santorini is complete and is the only pancreatic duct in this patient.

ment of serum calcium and plasma triglyceride levels, ultrasonography of the gallbladder and pancreas, and ERCP. The latter is of principal value in identifying ampullary stenosis (Fig 16) and anomalies of the pancreaticobiliary duct systems (Figs 17 through 19; see also Fig 15). We have found ultrasound examination of pancreatic duct size during pancreatic stimulation by secretin or morphine and prostigmine helpful for demonstrating functionally significant ampullary stenosis (Fig 20).244 CHRONIC

PANCREATITIS

PATHOGENESIS Alcohol abuse predominates as the most common cause of chronic pancreatitis in the West.202’ 2261“I The requisite quantity of alcohol necessary to induce chronic pancreatitis varies substantially, but a reasonable estimation is an average consumption of 150 ml/day for 20 years. There is no relationship between the type of alcohol or the pattern of consumption and the development of alcoholic pancreatitis. Despite the common toxic insult, a surprisingly small number of alcoholic patients with chronic pancreatitis concomitantly develop cirrhosis. It is not known whether this reflects different toxic injuries, different susceptibilities, or an epidemiologic artifact. Alcohol ingestion causes an increase in the protein concentration and bicarbonate concentration of pancreatic secretion.202 This pancreatic juice contains more protein precipitates than does the secretion from normal people, especially immediately after a period of alcohol abuse.g6 The changes in the composition of the pancreatic secretion cannot be explained by modifications of GI hormones and appear to be due to a direct toxic effect of alcohol on the pancreatic parenchyma. At least one of the proteins in the pancreatic secretion has a high affinity for calcium and may form a stable precipitate that remains within the smaller ducts. It has been hypothesized that these intraductal precipitates occlude the lumen and lead to atrophy of the epithelium, followed by inflammation and scarring of the parenchyma.202 Although widely accepted, the “protein plug” theory for the pathogenesis of alcoholic pancreatitis is, in fact, unproved by available evidence, and the precipitates may be harmless byproducts, rather than the cause of the disease. Gallstones are a frequent cause of acute pancreatitis but rarely of chronic pancreatitis. Residual scars due to pancreatic necrosis, abscess, or pseudocyst from the acute inflammatory episode may result in chronic lesions,123S 247 but, unlike what obtains in alcohol-induced pancreatitis, removal of the precipitating factor (by cholecystectomy) results in resolution or arrest of the disease. There is no documentation of gallstone-induced ampullary stenosis leading to chronic pancreatitis. 44

Fig 1 Il.-Transhepatic cholangiogram in a patient with ampullary stenosis associated with a duodenal diverticulum. She suffered recurrent attacks of acute pancreatitis.

Fig lg.-Endoscopic pancreatogram in a 22-year-old woman with a choledochal cyst and recurrent pancreatitis. The proximal portion of the pancreatic duct is dilated, and it inserts into the ampulla at an abnormal angle.

45

Fig PO.-Demonstration of ampullary stenosis by ultrasound before and after intravenous administration of secretin. A, baseline study showing the pancreatic duct with apposed walls and no open lumen (arrows). B, postsecretin study in a patient with pancreas divisum and accessory papilla stenosis: the pancreatic duct lumen (arrows) has increased to 2 mm along the entire length of the gland.

Metabolic factors more often produce acute rather than chronic pancreatitis. Hypercalcemia, predominantly due to hyperF,a;;thyroidism, can cause either acute or chronic pancreatitis, ’ but it probably accounts for less than 1% of all clinically recognized cases of chronic pancreatitis. Hyperlipoproteinemia may cause pancreatitis158; the levels of triglyceride necessary are usually quite high and usually in the form of chylomicrons. Trauma is a common cause of acute pancreatitis and may result in chronic disease if the major ductal system has been sufficiently disrupted. The literature includes reports on several types of hereditary 46

chronic pancreatitis with onset typically occurring in adolescence and affecting males slightly more frequently than females.276 Pancreatitis seems to be passed in an autosomal dominant fashion with incomplete penetrance. An aminoaciduria has been associated with the disease but is inconsistently found. Cystic fibrosis, an important cause of pancreatic insufficiency during childhood, rarely causes clinically recognizable pancreatitis. Chronic severe protein malnutrition may result in pancreatic insufficiency, especially in childhood.23 Steatorrhea is present, pain, inflammation, and endocrine insufficiency are absent, pancreatic ducts are normal, and fibrosis is uncommon. If fibrosis is not extensive, pancreatic function returns when nutrition is improved. Another form of pancreatitis which may be associated with malnutrition occurs in some tropical regions. It is almost endemic on the Indian subcontinent, particularly in the state of Kerala, where a limited vegetarian diet is common. In this form, recurrent abdominal pain begins in childhood. Pancreatic insufficiency, calcification, and diabetes are frequent and irreversible, even with improved nutrition. An increased prevalence of pancreatitis in persons with the congenital anomaly pancreas divisum has been recently demonstrated.l” Failure of the dorsal and ventral anlagen of the pancreas to fuse forces the major portion of the gland to drain via the smaller duct of Santorini and its accessory papilla. Clinical pancreatic disease is an uncommon sequela of this condition, but there is a fourfold increased risk of the development of acute, otherwise inexplicable pancreatitis. It may occur in individuals of both sexes and of all ages, but there is a greater incidence in young women. In most cases the clinical pattern is that of recurrent acute pancreatitis, but chronic pancreatitis is found in some patients and may be a direct consequence of long-term obstruction to the flow of pancreatic juice through an inadequate orifice at the accessory papilla. Unless there has been irreversible fibrosis of the gland, pancreatitis associated with pancreas divisum may be treated by a surgical sphincteroplasty263 of the accessory papilla. Other uncommon but identifiable causes of chronic pancreatitis include hemochromatosis, sclerosing cholangitis,23 and bilialso seems to be ary cirrhosis.78 In adults, chronic pancreatitis associated with choledochal cysts, probably because of a congenital malformation of the proximal pancreatic duct (see Fig 19).188 A substantial number of cases in which no etiology can be identified are unsatisfactorily grouped and described as idiopathic.233 PATHOLOGY Initially the gross appearance of the pancreas may be normal. Exacerbations cause swelling and inflammation; eventually the 47

Fig 21.-Endoscopic chronic pancreatitis. ampulla.

The

retrograde pancreatogram duct is markedly dilated

with

in a patient with relative narrowing

advanced near the

gland becomes indurated and scarred. Atrophy develops last, resulting in a shrunken pancreas with a firm, hard texture and a more tubular, rather than flattened, configuration. The islets of Langerhans become encased in fibrous tissue but retain adequate function until late in the disease. As the disease progresses the pancreatic ducts, which are initially normal, become increasingly distorted. Most characteristically there is dilatation of the duct (Fig 21>, sometimes interrupted by strictures. The duct may, however, be shrunken and constricted instead (Fig 22). It has not been determined whether the changes are primary, associated directly with the pathogenesis of the disease, or secondary to scarring from chronic parenchymal inflammation or duct disruption during episodes of acute Fig 22.-Pancreatogram case the duct is shriveled

48

in patient and distorted

with advanced chronic pancreatitis. by fibrosis along its entirety.

In this

Fig 23.-Multiple

calculi

in a dilated

pancreatic

duct

(intraoperative

photograph).

pancreatitis. Intraductal calculi (Fig 23), sometimes found in advanced pancreatitis, may be large enough to cause occlusion at the ampulla or at a stricture (Fig 24). CLINICAL PRESENTATION Abdominal pain is the cardinal titis. Although the inflammatory

symptom of chronic pancreadestruction and fibrotic re-

Fig 24.-Endoscopic pancreatogram in a patient pancreatitis. A ball-valve stone is lodged at a stricture the distal pancreatic duct is markedly dilated.

with painful in the head

chronic alcoholic of the gland, and

placement of the gland may have evolved insidiously over many years, the initial manifestation generally mimics an attack of acute pancreatitis.202’ 226,233 Early episodes may vary in duration from several hours to several days, but as the disease progresses, the attacks become more frequent and prolonged. Painfree intervals shrink and then vanish,” so that constant, severe pain is frequently the end-stage. Factors precipitating or directly exacerbating an attack are difficult to identify. Sporadic alcohol intake tends to provoke the pain 12-24 hours after the imbibing. The influence of meals is relatively insignificant, although eating may aggravate the discomfort, regardless of the composition of the meal, and prolonged fasting may relieve it. Antacids are ineffective, though relief may sometimes be gained by vomiting, or by sitting up and leaning slightly forward. The pain seems to worsen with fatigue. The mechanism of the pain in chronic pancreatitis is not well understood. The inflammatory reaction involving the pancreas and nearby parietal peritoneum is probably important in the early episodic form of the pain. Eventual entrapment of nerve fibers in scar tissue may cause the fixed chronic pain. It is also hypothesized, but unproved, that obstruction of the pancreatic ducts by strictures and intraluminal precipitates contributes to the pain. Although pain is the most common presenting symptom of chronic pancreatitis, it is not a sine qua n0n.i’ Asymptomatic chronic pancreatitis may be revealed by the incidental finding of pancreatic calcifications on x-ray studies or as a casual finding at laparotomy. Advanced disease may occasionally manifest as painless pancreatic insufficiency. When inflammation, atrophy, and fibrosis have reduced the pancreatic secretion of enzymes and bicarbonate to 10% of normal, there is significant maldigestion of fat and protein with consequent malabsorption of these nutrients and of fat-soluble vitamins, especially vitamin D.46, 67 The resultant steatorrhea causes frequent loose, foul, floating greasy stools, along with bloating, cramping, and flatulence. There may be an initial compensatory hyperphagia, but as the disease advances weight loss becomes the rule, both from malabsorption and from avoidance of food, induced by painful responses to eating. Some patients also develop deficiencies of water-soluble vitamins, especially vitamin B12. This defective absorption, which seems to be due to a binding of vitamin B12 to nonintrinsic factor golypeptides, is reversed by replacement of pancreatic enzymes.23 As pancreatic insufficiency develops and bicarbonate secretion falls, the intraduodenal pH rises. Consequently there is an increased incidence of duodenal ulcer in these patients. This possibility should be investigated, particularly in patients with postprandial pain.210 50

Approximately one third of patients with chronic pancreatitis will have overt diabetes mellitus and another third develop abnormal glucose tolerance. The first manifestation will be transient hyperglycemia, most often associated with an episode of acute pancreatitis or an exacerbation of pain. Overt diabetes mellitus usually evolves in the second decade, after the onset of other symptoms, but it can be the presenting feature in patients with painless chronic disease. Because the islets of Langerhans have a greater resistance to injury by inflammation and fibrosis than the exocrine tissues, most patients who develop diabetes will already have pancreatic exocrine insufficiency and steatorrhea. Patients with chronic pancreatitis may present with a tender epigastric mass due to a pseudocyst. Other complications such as obstructive jaundice,‘i7, 264gastric outlet obstruction,38’ 4o pancreatic ascitesj3’ ” or leural effusions,53 and upper GI tract bleeding from varices13 F:are uncommon in early stages.

PHYSICAL EXAMINATION There are few pertinent physical findings in most patients with chronic pancreatitis. The commonest is a weight loss proportional to the severity of anorexia and steatorrhea. Tenderness in the upper abdomen is common, especially in the presence of acute inflammation. An enlarged pancreas is occasionally palpable, especially in a thin person, but the finding of a mass may indicate a pseudocyst. Rare findings include jaundice secondary to a stricture of the common bile duct, an enlarged spleen secondary to thrombosis of the splenic vein, ascites secondary to a pancreaticoperitoneal fistula, or a gastric succussion splash secondary to duodenal obstruction.

LABORATORY STUDIES Diagnosis of chronic pancreatitis, especially in earlier stages or milder forms, is made difficult by the lack of a specific laboratory test. Serum amylase and lipase levels contribute to the diagnosis of acute pancreatitis but are less useful in the evaluation of chronic pancreatitis.i7 Serum levels of these enzymes rise with acute exacerbations of inflammation or pancreatic duct obstruction, but usually remain normal in uncomplicated chronic pancreatitis. Analysis of amylase isoenzymes in serum or urine shows the pancreatic isoamylase to be decreased in chronic pancreatitis. The decline of circulating pancreatic isoamylase is an insensitive index for the disease, however, because it seems to occur only in moderately advanced stages with considerable loss of functioning tissue. Abnormal “aged” pancreatic isoamylases, altered during stagnant incubation, are found in pseudocysts and in the serum of patients with pseudocysts. 51

Tests reflecting the loss of pancreatic function have been used to detect chronic pancreatitis. Examination of the stool for neutral fat with the Sudan stain provides a crude qualitative test for pancreatic insufficiency. It is more precise to measure the fecal fat excretion over 72 hours on a diet of defined fat intake. If there is steatorrhea, maldigestion due to pancreatic insufficiency may be differentiated from malabsorption due to intestinal disease by normal D-XylOSe absorption or partial reversal of the steatorrhea with oral replacement of pancreatic enzymes. Severe pancreatic exocrine insufficiency may also be documented by measurement of reduced fecal chymotrypsin. The protein lactoferrin is increased in pancreatic secretions in chronic pancreatitis, and its measurement may be used to diagnose chronic pancreatitis. 16i No currently available noninvasive tests for chronic pancreatitis are sufficiently sensitive to detect mild disease or sufficiently specific to exclude other related diseases 11,66,122 Direct measurement of pancreatic secretory capacity provides The secretin a more sensitive index of pancreatic function. test, which measures the flow of pancreatic fluid, bicarbonate, and enzymes into the duodenum in response to a standard dose of secretin, is used to show glandular insufficiency or duct obstruction. Pancreatic exocrine function may also be quantified by the Lundh test,” in which the patient consumes a standard meal designed to stimulate the production sf endogenous secretin and cholecystokinin. Endocrine pancreatic function can be estimated using the fasting and 2-hour postprandial blood glucose levels or more precisely quantitated with a glucose tolerance test. Biochemical tests of liver function may suggest biliary obstruction from stricturing of the lower common bile duct caused by surrounding fibrosis. The serum alkaline phosphatase level is the most sensitive index, an increased level occurrin in as many as one third of patients with chronic pancreatitis.26 B’ 264 As the bile duct obstruction worsens or secondary biliary cirrhosis develops, the serum bilirubin level also rises. Fluctuation in the serum bilirubin level occurs as well with superimposed bouts of pancreatic inflammation or with recurrent cholangitis.264 RADIOGRAPHY

The advent of complex radiographic techniques has not diminished the value of plain films of the abdomen in the detection of chronic pancreatitis.215 Pancreatic calcifications are found in 30% of patients at relatively early stages of the disease and in 50%-60% of patients with advanced disease (Fig 25). Barium contrast studies are not helpful unless duodenal stenosis or coincident alimentary disease such as duodenal ulcer is suspected. Ultrasonography has proved invaluable in the diagnosis of cer52

Fig 25.-Calcification in the pancreas. A, plain radiograph of the abdomen demonstrating large calcifications in the pancreas of a patient with chronic alcoholic pancreatitis. B, cut section of a pancreas in chronic calcific pancreatitis. The calcifications are shown to be stones lodged in the ducts.

tain aspects of chronic pancreatitis,17’ lz7, lg7 particularly the demonstration of pseudocysts. The gland itself is usually close to normal in size and configuration but may show swelling or even a mass when there is active inflammation. The newer real-time instruments allow the detection of dilatation of the pancreatic duct. The major limitation of ultrasound is incomplete imaging due to overlying intestinal gas. Ultrasonography has largely replaced selenomethionine radionuclide scanning of the pancreas as a noninvasive test.lg The radioisotope scan has an unacceptably high frequency of false positive results, but because of its low false negative rate, about lo%, it is still used by some to rule out pancreatic disease. CT offers better resolution than ultrasonography and is not 53

limited by inability to image through bowel gas.‘l’ g8 However, because CT relies on contrast of tissue density, particularly fat, good imaging may be difficult in emaciated patients. Physicians using either ultrasonography or CT may have occasional difficulty in differentiating chronic pancreatitis from pancreatic carcinoma. l4 If cancer is suspected, percutaneous “skinny needle” aspiration to obtain cytologic aspirates will provide cytologic proof of malignancy in nearly 90% of pancreatic cancers, and false positive findings are rare.28o Detailed information about the anatomy of the pancreatic ducts sufficient for planning operative therapy generally cannot be gleaned from scanning techniques alone. Direct opacification of the pancreatic ducts with contrast material, accomplished by ERCP,“, 83 demonstrates a normal appearance in early stages. Abnormalities regularly observed in moderate or advanced disease163 are an initial irregular dilatation of the main pancreatic duct with occasional narrowing or diffuse constriction and pruning of the ductal system (Fig 26), followed by the several-fold dilatation of the main pancreatic duct (see Fig 21). There may be segmental constrictions (“chain of lakes”) or even complete obstruction, sometimes by an intraluminal stone. Often the entire duct is narrowed, with pruned secondary branches. Extrinsic compression of the segment of common bile duct within the substance of the pancreas occurs in up to one third of patients with moderate or advanced chronic pancreatitis.262, 264 Cholangiography by the endoscopic retrograde or the percutaneous transhepatic route demonstrates the typically long, tapered, smooth stricture of the intrapancreatic portion of the bile Fig 26.-Pancreatogram pancreatic duct.

showing

mild dilatation,

tortuosity,

and irregularity

of the

duct (Fig 27). Cholangiography is indicated in any chronic pancreatitis patient with jaundice or a persistently elevated serum alkaline phosphatase level. Selective celiac angiography is used primarily when occlusion of the splenic or portal vein (Fig 28) is suspected, or to document vascular anatomy in preparation for major surgical resections.13’ NATURAL HISTORY

Chronic alcoholic pancreatitis tends to become symptomatic in early adulthood after lo-20 years of heavy alcohol abuse. Patients usually present with acute abdominal pain and the clinical features of acute pancreatitis. Physiologic or histologic studies, however, will demonstrate established chronic pancreatitis even at presentation.‘02 Although the first attack of pain generally resolves completely, continued alcohol abuse leads to relapses of pain or acute pancreatitis. Successive attacks are less dependent on alcohol ingestion and slower to resolve. Significantly elevated serum amylase levels are found only during early acute attacks. Later, levels remain normal even during symptomatic exacerbations. After a mean of 5-8 years, discomfort diminishes in many patients, a development which is believed to indicate the onset of pancreatic exocrine and endocrine

Fig ST.-Cholangiogram demonstrating a stenotic distal common bile duct due to chronic pancreatitis. The stenosis is caused by pancreatic fibrosis surrounding and constricting the duct as it traverses the head.

55

Fig 28.-Superior mesenteric angiogram showing obstruction mesenteric and portal veins in a patient with chronic pancreatitis. vein (large arrow) terminates in a nest of variceal collateral veins

of the superior The mesenteric (small arrows).

insufficiency, indicative of “burning out” of the pancreas.i’, i2, 88 The appearance of calcifications on abdominal radiographs has been proffered as a similar herald of the abatement of pain; however, our experience does not substantiate this as a clinically useful observation. The role of abstinence in the treatment of chronic pancreatitis is unproved, but common wisdom emphasizes its importance in limiting the recurrence of acute pancreatitis early in the disease.i” 35 Later on, pancreatic insufficiency progresses relentlessly even with faithful abstinence from alcohol. The secondary diabetes of chronic pancreatitis is associated with a much lower incidence of vascular degenerative complications such as retinopathy, nephropathy, and g;ripheral arterial atherosclerosis than is spontaneous diabetes. It is not known whether this is a function of the shorter duration of this form of diabetes, due to its later onset and decreased longevity, or whether genetic factors that may be associated with idiopathic diabetes and which cause its complications are absent in the diabetes of chronic pancreatitis. Most patients survive at least two decades following the initial appearance of symptoms of chronic pancreatitis. Most deaths are due to cardiovascular, malignant, or hepatic disease; rarely are they directly related to pancreatitis per se or its complications. The incidence of cancer of the pancreas itself is probably not significantly increased in patients with chronic pancreatitis, with a probable exception in the rare kindreds with hereditary pancreatitis. 56

COMPLICATIONS

At least 10% of patients with pancreatitis develop clinically apparent pseudocysts.41T 63, ‘W Pseudocysts are collections of escaped pancreatic fluid and liquefied tissue which form in pancreatic or peripancreatic tissues, encased by walls of granulation and fibrous tissue not lined by epithelium. Two kinds of pseudocysts are known: those formed as sequelae of injury to the pancreas, occurring during an acute episode of pancreatitis; and those appearing in chronic pancreatitis without an identifiable antecedent attack of inflammation and which are thought to be related to obstruction of the duct by a stricture or pancreatic calculus.63 Varying in diameter from 1 to 20 cm, pseudocysts may be found within the gland or outside it, from the neck to the pelvis. The propensity of pseudocysts to track widely throughout the retroperitoneum and out into the mesenteries, up into the thorax, and to develop fistulas into viscera is thought to be consequent of erosion by the activated proteolytic enzymes in the cyst contents. Pseudocysts most commonly present with a characteristic epigastric pain, which is frequently aggravated by eating. Vomiting or jaundice, caused by impingement on the stomach or duodenum or on the bile duct, and fever may amplify the presentation. Conversely, an asymptomatic pseudocyst may be discovered during palpation or even as an unanticipated finding on ultrasound or CT scans (Fig 29) or on ERCP. Our appreciation of the natural history of pseudocysts is changing in response to new diagnostic techniques, particularly ultrasound and CT, which have demonstrated silent cysts and spontaneous resolution of pseudocysts. An estimated 30% of pseudocysts consequent on an attack of acute pancreatitis reFig 29.-CT

scan

showing

a large

mature

pancreatic

pseudocyst,

solve spontaneously within 6 weeks of the attack,41 after which time the chances of resolution of larger cysts is markedly diminished. Spontaneous resolution rarely occurs with pseudocysts in chronic pancreatitis if there has been no identifiable superimposed acute attack. In a 4-year experience at the Massachusetts General Hospital, none of 27 “chronic pseudocysts” resolved during a minimum of 4 weeks’ observation. The acute life-threatening complications of pancreatic pseudocysts are rupture into the free peritoneal cavity, rupture into a viscus (usually with lethal hemorrhage into the GI tract), evolution into a pancreatic abscess, and erosion of a major blood vessel with massive hemorrhage into the pseudocyst cavity. Avoidance of these consequences is the primary motivation behind the surgical treatment of symptomatic, persistent pseudocysts, especially those greater than 5 cm in diameter. In a series of 93 patients with pseudocysts, primarily caused by acute pancreatitis, the incidence of complications in medically treated patients was 41%, compared with a 20% incidence of complications in surgically treated patients.41 Pseudocysts arising in chronic pancreatitis are much less often associated with major signs of inflammation or spontaneous complications: none occurred in the 27 patients mentioned above. The surgical treatment of chronic pseudocysts should be attended by a morbidity well under 5%. Fibrotic pancreatic tissue surrounding and encasing the distal several centimeters of the common bile duct can cause a lengthy stricture of the duct (see Fig 27) in as many as one third of patients with known chronic pancreatitis.‘i “03 Compression of the duct by an adjacent pseudocyst can also cause Jaundice, but irreversible fibrosis of the duct is usually present.26 The earliest functional consequence is simple cholestasis, which, if left untreated, can lead to secondary biliary cirrhosis.264 Although there is an initial persistent increase of the serum alkaline phosphatase level, followed by hyperbilirubinemia, bilirubin levels and clinical jaundice can fluctuate during periods of active pancreatic inflammation or low-grade cholangitis.264 Some patients with previously asymptomatic chronic pancreatitis may first present with obstructive jaundice which, especially in the absence of accompanying pain, can easily be misdiagnosed as cancer. Obstruction of the upper GI tract is much less common than biliary obstruction, but fibrotic strictures of the second portion of duodenum do occur (Fig 30).40 Pseudocysts in the head of the pancreas will occasionally compress the duodenum or pyloric antrum and may cause transient obstruction of the duodenum. Ascites in an alcoholic patient is correctly attributed to hepatic cirrhosis in most cases. However, in chronic pancreatitis it may be due to a direct communication between the pancreatic 58

Fig 30.4rreversible titis.

obstruction

of the duodenum

by fibrosis

in chronic

pancrea-

duct system and the peritoneal cavity, usually the consequence of a ruptured pseudocyst, but sometimes due to rupture and necrosis of a duct near the surface of the gland.53’ w 2og These patients present with ascites, with or without chronic pain, but without an acute abdominal catastrophe. Paracentesis can establish the diagnosis of chronic pancreatic ascites by the presence of very high concentrations of amylase in the ascitic fluid, a protein concentration greater than 3 gm/dl, and a leukocyte count greater than 1,000/mm3. The pancreaticoperitoneal fistula can be shown in most cases by endoscopic pancreatography.135 Chronic pleural effusions may develop by a mechanism similar to that just described.53 The pancreatic secretions from a ruptured pseudocyst or pancreatic duct leak into the retroperitoneum and dissect cephalad through the esophageal foramen, or behind the attachments of the diaphragm, into the chest and into the pleural space. Fistula into the pericardium occurs as well. These patients present with dyspnea and cough due to a large effusion, usually unilateral and more often on the left. In contrast to the pleural effusions that may follow an attack of acute pancreatitis, there is usually no recent acute episode antecedent to the development of chronic pancreaticopleural effusions. They do not resolve spontaneously, and they recur rapidly after thoracentesis. The diagnosis is established by a very high amylase concentration in the effusion and by demonstrating the pancreaticopleural fistula with ERCP (Fig 31). Obstruction of the portion of the splenic vein that lies within the pancreatic substance may occur due to fibrosis or thrombosis caused by continuous inflammation.i3’ Splenomegaly usually develops slowly and remains asymptomatic, as the gastric veins 59

Fig N.-An endoscopic retrograde pancreatogram periorly toward the esophageal hiatus from a ruptured tied into the left pleural space and produced a chronic

showing a fistula tracking supseudocyst. The fistula empeffusion.

provide adequate collateral venous drainage. In some cases, however, hypersplenism or acute rupture of the spleen may occur. Localized portal hypertension in the gastric wall may lead to gastric varices, but these rarely rupture or bleed. Less commonly, the portal vein itself becomes obstructed, either by propagation of thrombus from the splenic vein or by constriction of the portal and superior mesenteric veins as they course through the pancreas (see Fig 28). This circumstance produces more generalized portal hypertension and is more likely to lead to bleeding esophageal varices.13g, i5’ Of 14 patients in whom this has happened-six described in the literature and eight of our own-eight have had major variceal hemorrhages. Erosion and weakening of the arterial walls by inflammation and enzymatic digestion may produce false aneurysms of the arteries in and around the pancreas, most often the splenic, gastroduodenal, and pancreaticoduodenal arteries. In acute pancreatitis this occurs during the active necrotizing phase of the attack or later in an abscess cavity, while in chronic pancreatitis it occurs in association with a pseudocyst. Rupture of the aneurysm causes hemorrhage into the cyst cavity that is massive but can be intermittent, Blood may reach the intestinal tract via the pancreatic duct and present as GI tract bleeding.141 Angiography can identify the bleedins vessel and facilitate control of ‘i Definitive treatment for the hemorrhage by embolization. pseudocyst and ligation of the communicating artery must be accomplished surgically. 60

MEDICALTHERAPY

The treatment of chronic pancreatitis begins with the identification of etiologic factors and their correction, when possible, in order to limit progression of the disease. Unfortunately, alcoholic pancreatitis can be particularly resistant to therapy because the stubborn nature of alcohol abuse often delays the seeking of treatment until it is too late for treatment to be of substantial benefit. If the symptoms are still intermittent, abstinence may be rewarded. However, as the periods of pain become more frequent and merge into continuous discomfort, the likelihood of significant improvement diminishes.206 At this point, the pain seems to become established and often to progress unremittingly even without further alcohol ingestion. Common sense dictates, however, that any patient with chronic pancreatitis should restrict alcohol consumption severely. Once the limitation of toxic factors is accomplished, treatment is directed at the manifestations and complications of chronic pancreatitis. No present means exists to relieve or even to halt the inflammation and scarring of the gland. Episodes of acute pancreatitis should be treated as discussed previously. In any stage of chronic pancreatitis pain control is likely to be the major problem, as pain is often unresponsive to aspirin or nonsteroidal anti-inflammatory drugs and requires narcotics. Codeine or meperidine are suitable for intermittent use, but methadone is better for long-term maintenance analgesia. The demands of habituation or addiction become so closely entwined with those of the pain of the disease that it becomes nearly impossible to differentiate between the two. Decreased stimulation of the pancreas has been attempted by following low-fat diets, using anticholinergic medications, and by using oral pancreatic enzymes to reduce pancreatic pain by feedback inhibition of pancreatic secretion, but there is little evidence that pancreatic secretion is thereby lessened, or pain decreased. Splanchnic nerve block with alcoho1ioo7 133 has been effective in only 15%-20% of patients with persistent severe abdominal pain, and the pain tends to return after several months. It is therefore more useful in the short-term treatment of pancreatic cancer than in the treatment of chronic pancreatitis. The possibility should be explored that the pain may be due to a treatable complication of pancreatitis such as a pseudocyst, or a coincidental treatable disease such as a peptic ulcer. Nutritional support is a critical element in the management of patients with chronic pancreatitis. Pancreatic exocrine insufficiency and steatorrhea are preceded in many patients by periods of anorexia, nausea, and vomiting with a concomitant decrease in protein and calorie intake. This problem is magnified in alcoholic patients with irregular eating habits. Diets that are rich in carbohydrates and somewhat restricted in fat and protein 61

are better tolerated,230 and care should be taken to anticipate and treat vitamin deficiencies (such as B2, B12, and D). When pancreatic exocrine function falls below 10% of norma& steatorrhea develops and malnutrition becomes significant. Initially, increased caloric intake may partially compensate. Further benefit may be gained from oral replacement of pancreatic enzymes, especially those rich in pancreatic lipase, to limit steatorrhea. Treatment usually begins with two tablets of pancreatin with each meal and one tablet with each snack,65S g3 the dose increasing until symptoms of diarrhea and flatulence are controlled. Although malabsorption should theoretically be abolished by the replacement of lo%-20% of normal enzyme activity in the duodenum, this rarely occurs, apparently because of inactivation of enzymes by gastric acid and insufficient mixing of food and pancreatic enzymes.68 The efficacy of enzymes is improved by the coincident administration of antacids, especially aluminum hydroxide or sodium bicarbonate,g4 or Hz-receptor antagonist drugs.“’ Microencapsulated enteric-coated preparations of pancreatic enzymes are an expensive alternative to adjuvant antacids. While the diabetes complicating chronic pancreatitis may initially be responsive to careful attention to overall good nutrition43 and dietary control, oral hypoglycemic agents or insulin therapy are often ultimate1 required. There is some propensity to hypoglycemic attacks,’ B’ perhaps due in part to irregular food intake during episodes of abdominal pain or anorexia, and perhaps to impaired release of glucagon. Diabetic ketoacidosis is not often seen except after major pancreatic resections. SURGICAL THERAPY The most common indication for operation in chronic pancreatitis is abdominal pain refractory to medical therapy,245, 274 which is present in more than 90% of cases. Of our last 50 patients operated on for this disease, 49 had pain as a major symptom. Complications of chronic pancreatitis, such as obstruction of the common bile duct or duodenum or the persistence of a pancreatic pseudocyst, are present in 35%-40% of patients and occasionally occur without pain. Although the pain may in some cases “burn out” as the gland deteriorates, loses function, and to require that a patient wait calcifies,l” ” it is unreasonable years for possible spontaneous relief if an adequate surgical solution exists.245 The tactics of the two major surgical alternatives for reducing pancreatic pain are either improvement of drainage of the pancreatic duct or resection of pancreatic tissue.8’ 177 Drainage (decompressive) procedures are preferable because they are safer, relatively simple, and conserve pancreatic tissue and residual 62

exocrine and endocrine function; however, they require the presence of a dilated pancreatic duct, usually greater than 7 mm.202’ 204 ERCP has become an invaluable tool for demonstrating the size and configuration of the pancreatic ducts and thereby for planning the best surgical approach.278 In 30%-40% of patients failing medical therapy the main pancreatic duct will be dilated, usually without obvious evidence of obstruction, even though the duct be three to four times its normal diameter. Functionally significant strictures and obstructed segments occur in the minority. If the main duct is over 7 mm in diameter, it is opened along its length for as long a distance as is feasible, preferably S-10 cm, and a Roux-en-Y loop ofpjunum is sutured to it (modified Puestow procedure, Fig 32). 17’, ‘17 274,275 Long-term follow-up has demonstrated continued patency of the anastomosis in up to 100% of cases261 and effective pain relief in more than 70% of casesi2” ‘7’s 2049274,275 at a cost of almost no surgical mortality. In a personal series of 37 patients, over 80% take no pain medication. There was only one complication or postoperative death, which occurred in a patient with coincident end-stage cirrhosis and portal hypertension. The mechanism of pain relief by pancreaticojejunostomy in the absence of objective evidence of obstruction is unclear, but may be a function of relieving impeded drainage and high intraductal pressure.3g Although no pancreatic tissue is sacrificed and the gland is adequately decompressed, pancreatic insufficiency develops eventually in at least 35% of patients due to continuing deterioration of acinar tissue.261 Caudal pancreaticojejunostomy (Duval procedure), in which the transected tail of the pancreas is anastomosed to a Roux-en-Y loop of jejunum for retrograde drainage, is less successful than lateral anastomosis because the connection is too small to decompress the entire length of gland effectively and is more likely to occlude in time.lzg Transduodenal sphincteroplasty is generally ineffective Fig 32.~-Side-to-side pancreaticojejunostomy (modified Puestow procedure). A, Roux-en-Y loop of jejunum is sutured to the fileted pancreas with an outer layer of interrupted silk sutures. 6, inner layer of continuous polyglycolic acid suture joins the jejunal mucosa to the pancreatic duct mucosa.

63

for chronic pancreatitis because the treated segment is too short to allow decompression of the greater portion of the pancreatic duct. Patients whose main pancreatic duct is not dilated are not candidates for pancreaticojejunostomy. Resection of the distal 50%-60% of the pancreas has been done, with little success. The principal indication for this operation is the treatment of patients with obstructing lesions of the midpancreatic duct (see Fig localized 14) lz3, 247 and the rare situation of chronic pancreatitis to the distal portion of the gland. Distal subtotal (95%) pancreatectomy (the Child procedure) has had somewhat better success in relieving severe chronic pain.84 In this operation all of the pancreas is resected except for a small amount of tissue along the sweep of the duodenum. It is said by some to be effective for the relief of pain 50%-60% of the time, although virtually all patients develop pancreatic insufficiency and diabetes. Especially if the pancreatitis appears to be disproportionately localized to the head of the pancreas, perhaps with a mass, resection of the head (pancreaticoduodenectomy, the Whipple procedure) may be the best alternative.60, 15’ Pancreaticoduodenectomy is a complicated operation, more difficult in these patients than in patients with cancer, and requires special skills, but in appropriately selected patients the rate of satisfactory pain relief exceeds 70%. Enough pancreas is preserved so that many patients do not immediately develop diabetes. The popularity of this option appears to be waxing. We favor preservation of the antrum and pylorus, as described by Traverso and Longmire,141A and have performed the operation in eight patients, with good results in seven. Gall et al. have championed the technique of obliterating the pancreatic duct by filling it with a substance that hardens.85 This maneuver is intended to potentiate the pain relief of the Whipple operation by inducing atrophy of the exocrine pancreas and also to increase the safety of the pancreaticojejunal anastomosis. It has not been widely adopted. Total pancreatectomy is the procedure of last resort.36 Although relief of pain is usually achieved, pancreatic insufficiency and brittle diabetes are inevitable. Without endogenous glucagon, insulin reaction and profound hypoglycemia are greater threats than hyperglycemia and ketoacidosis. Because diet and insulin must be carefully and regularly controlled, unreformed alcoholics are not candidates for total pancreatectomy, which carries a high risk of death from acute complications of diabetes. If transplantation of the pancreas proves to be practical, it may considerabl reduce the morbidity of total exocrine pancreatectomy.55’ 164,2J3 Vagotomy and antrectomy with a Billroth II gastrojejunostomy has been used in some patients,17* with the rationale of reducing the normal stimulation of pancreatic secretion by duo64

denal hormones, gastrin, and the vagus. This approach has had occasional success, particularly in those patients whose pain is aggravated by eating, and may preclude the need for major pancreatectomy. We have identified only one or two patients in our own practice who seemed to fit this description. Patients with the congenital anomaly pancreas divisum are at increased risk of developing acute recurrent pancreatitis because of a stenosis at the orifice of the duct of Santorini, which functions as the main pancreatic duct in these individuals.“’ This obstruction m&ht in some patients lead to permanent damIf the disease is sufficiently early in its age to the gland. course, recurrent pancreatitis is prevented by transduodenal sphincteroplasty of the accessory ampulla.263 If chronic fibrotic pancreatitis has become established, sphincteroplasty is no longer adequate. Treatment necessarily becomes more complex and follows the principles outlined previously for other forms of chronic pancreatitis. If the stenosis of the distal common bile duct by extrinsic compression and fibrosis (see Fig 27)217, 264 has functional significance, the serum alkaline phosphatase level will be raised. Later, jaundice and eventually secondary biliary cirrhosis may develop. Decompression of the bile duct by choledochoduodenostomy or choledochojejunostomy is indicated when a significantly elevated alkaline phosphatase level persists, hyperbilirubinemia supervenes, or liver biopsy shows evolution toward cirrhosis. In our personal series, we have used choledochoduodenostomy in 20 cases, with one recurrent biliary stricture in 10 years’ follow-up. Choledochojejunostomy was chosen in seven cases, and there have been no late complications. Anastomosis using the gallbladder as the conduit instead of the common duct was used several times in our earlier experience, but two patients developed chronic stasis and stones requiring cholecystectomy and choledochoenteric bypass. Obstruction of the duodenum in chronic pancreatitis may be due to progressive and unremitting fibrotic narrowing rather than to transient edema, as in acute pancreatitis. It is treated by bypass with a gastrojejunostomy. We have not felt it necessary to perform a complementary vagotomy in the absence of peptic ulcer disease. Pancreatic pseudocysts associated with chronic pancreatitis or with resolving acute pancreatitis should be treated surgically if symptomatic, larger than 4 cm, or persistent for more than 6 weeks.41’ ‘I2 Internal drainage to the stomach (Fig 331, duodenum, or a Roux-en-Y loop of jejunum is preferred.2127 241p2’8 Results of each of the three approaches have been similar: recurrence after cyst-enterostomy is about 5% and postoperative bleeding is well under 5%. The choice of tactics is most simply predicated on proximity-the hollow viscus (excluding the colon) nearest the pseudocyst can be used for the anastomosis. In our 65

Fig 33.-Drainage of a pseudocyst by cyst-gastrostomy. A, the position of the cyst behind the posterior gastric wall is confirmed by needle aspiration through the opened stomach. B, the opening through the posterior gastric wall has been made as large as possible. Interrupted nonabsorbable sutures have been placed circumferentially both for hemostasis and to ensure that the opening persists.

practice large pseudocysts are most frequently drained into the stomach and smaller ones into a Roux-en-Y loop. External drainage, used when the cyst wall is too flimsy to hold sutures, is associated with a high recurrence rate of 25%. Percutaneous catheter drainage of pseudocysts is being studied as a definitive treatment; preliminary results show an unacceptably high frequency of infection and recurrence of the cyst. Chronic pancreatic ascites and pleural effusions, caused by an internal fistula from the pancreas to the peritoneum or pleural space, occasionally respond to repeated withdrawal of the fluid and pharmacologic reduction of pancreatic secretion with acetazolamide and anticholinergic drugs. In such cases the point of leak has healed spontaneously. In most cases, surgical treatment is necessary. 3 The location of the leak from the pancreatic duct, usually due to a ruptured pseudocyst, can be demonstrated by ERCP (see Fig 31) in more than 80% of cases.135 The most common surgical tactic used to treat pancreatic ascites is to bring a Roux-en-Y loop of jejunum up to the site of the leak to channel the pancreatic secretions into the intestinal tract. When the disruption is in the tail of the pancreas, distal pancreatectomy may provide a simple and effective solution. In patients with pancreatic pleural effusions, the retroperitoneal fistula into the chest can be interrupted below the diaphragm (Fig 34). Once the origin of the fistula has been dealt with, nothing need be done to the pleural end of the tract other than emptying the fluid from the pleural cavity. The interrupted fistula tract will heal and the pleural effusion will not reaccumulate. Frequently more than one indication for operation exists (Table 5). Pseudocysts are present in about one fourth of all patients requiring operation for chronic pancreatitis, and bile duct sten66

Fig 34.-Schematic diagram showing (left) a dilated pancreatic duct, with a distal pseudocyst and pancreaticopleural fistula. It was treated surgically (right) by side-toside pancreaticojejunostomy (modified Puestow procedure) and ligation of the fistula tract.

oses occur in about 30%. Duodenal obstruction, less common, is apparent in about 5%. Pancreatic ascites is quite uncommon, and pancreatic pleural effusion is downright rare. The surgical plan must deal with as many of these problems as necessary. Combined drainage of multiple organs-pancreatic duct, bile duct, stomach-into the jejunum is effective and not difficult. When obstructed drainage systems can be thus identified and treated, the remaining pancreatic tissue can be maximally conserved, rather than resected. Implicit in this approach is the concept that no one operation is universally applicable. Different strategies will be best suited to each case, depending on the particular pathologic anatomy. TABLE IN

L-INDICATIONS FOR SURGICAL TREATMENT 58 CONSECUTIVE PATIENTS WITH CHRONIC PANCREATITIS

INDICATION

With dilated pancreatic duct (> 7 mm) Pain + bile duct obstruction + duodenal obstruction + biliary and duodenal obstruction + pseudocyst Bile duct obstruction (painless) Without dilated pancreatic duct Pain + bile duct obstruction + duodenal obstruction + pseudocyst

NO.OF ETS.

(38) 37 21 1 3 8

(2:)

20 0 0 4 67

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ANSWERS

1. a 2. 3. 4. 5.

e e a b

TO SELF-ASSESSMENT

6. 7. 8. 9.

QUESTIONS

c c b a

10. e

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