Inflammatory Diseases of the Brain

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INFLAMMATORY DISEASES OF THE PANCREAS Author:

John A. Lott Department of Pathology Ohio State University Columbus, Ohio

Rcfene:

H.-D. Gruerner Section of Clinical Chemistry Medical Collcgc of Virginia Richmond, Virginia

I. SCOPE OF REVIEW

.

A large section of this review deals with the laboratory findings in pancreatitis. The laboratory findings in pancreatitis continue to be expanded, and more sensitive and specific tests appear to be on the horizon. Pancreatitis and its etiology, mechanism, treatment, etc. have been the subject of a number of reviews and monographs.’-23The most recent literature on pancreatitis has been summarized here. The pancreas is a small gland, about the size of the hand, which is behind the stomach and is nestled into a loop of the duodenum. Its head points to the right and down, and the tail terminates close to the spleen. There is no question that the pancreas plays as important a role in maintaining the homeostatic mechanisms of the body and normal body function as does the pituitary. The origins of exocrine pancreatic enzymes are the acinar cells, while electrolytes and water come primarily from the centroacinar or ductal cells. The pancreas, when acutely inflamed owing to any number of causes, appears to produce a toxic substance(s) which can affect organs remote from the pancreas such as the brain, lung, heart, liver, and kidneys. Inflammatory disease of the pancreas can be catastrophic if it evolves into acute hemorrhagic necrosis of the gland, and the mortality of the latter approaches 100%. How hemorrhagic necrosis develops is not well understood; there are many theories for the pathogenic cascade, but the data are very sparse from humans with the disease which could elucidate the mechanism, A number of substances have been identified as the putative toxin that is elaborated by the inflamed pancreas. Animal experiments done with such toxins are often unconvincing owing not only to the species differences, but owing to the extraordinary conditions which must be used in animals to show a toxic effect. For example, to prove that high triglyceride concentrations can cause secondary injury to lung, one group of investigators infused an emulsion containing 10% by volume triglycerides into the pulmonary artery of dogsZ4Not surprisingly, they saw injury to the lungs, however this model hardly resembles what occurs in the human disease. Some animal models of pancreatitis mimic the human disease, however the way pancreatitis is induced is often extraordinary, e.g., infusing of trypsin and bile salts into the pancreas,” and this is probably unlike what triggers pancreatitis in humans. Certainly the major cause of pancreatitis, chronic alcohol abuse, has not been reproduced in an animal model. Other purposes of this review are to define terms, to list the major believed causes of pancreatitis, and to describe a proposed pathogenic cascade that can occur in pancreatitis from the mild edematous form to the disastrous full-blown fulminant disease where hemorrhagic necrosis and infarction are seen. The emphasis of the review is on the use of laboratory data to make the diagnosis. It is obvious from the


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discussion here that a diagnosis of acute or chronic pancreatitis cannot be made from laboratory data alone. The correct diagnosis of pancreatitis is still an important challenge to the clinician, since some patients who present with an “acute, abdomen” and even with abnormal pancreatic enzymes in serum do not have pancreatitis. Those conditions which mimic pancreatitis are described here briefly. The diagnosis of pancreatitis must rely on all the available historical, laboratory, clinical, radiological, and other information. A section is included here on the possible toxic agent(s) released from the inflamed pancreas. Possibly if they could be identified, the therapy might be more specific and effective, and the progression to hemorrhagic necrosis might be averted in some patients. The evidence for a toxic substance(s) is very strong in view of the much better survival of patients treated with peritoneal lavage. Medical and surgical treatments are not discussed here as they have been described in detail elsewhere.’1*’2~16*23 What the “best” treatment is remains controversial. Antiproteases, glucagon, and antibiotics have been shown to be without value. The only fairly new treatment which appears to reduce early mortality is peritoneal lavage.’’ When a new treatment protocol is proposed, it is often difficult to evaluate it in a clinical study owing to the ethical and moral problems of withholding a possibly life-saving procedure in a patient with a bad prognosis. Diabetes mellitus, the major endocrine disease of the pancreas, is discussed here only as a sequel to long standing chronic pancreatitis where the gland has been destroyed. Patients with diabetes occasionally have abnormal serum amylase and lipase activities particularly if diabetic ketoacidosis is present. Only rarely are these patients believed to have pancreatitis.

11. DEFINITION OF TERMS At the 1963 Marseilles Conference on Pancreatitis, four categories of pancreatitis were proposed:’’ 1. Acute pancreatitis Recurrent acute pancreatitis 3. Recurrent chronic pancreatitis 4. Chronic pancreatitis 2.

The distinction between acute and chronic inflammation was made on the basis of recovery of the gland of its structural and functional integrity after a bout of the disease. During the recovery phase following acute or recurrent acute pancreatitis, there is healing of the gland and restoration to its normal state as judged by its exocrine and endocrine functions and judged by its gross and microscopic anatomy. Pancreatic insufficiency and diabetes mellitus is absent, assuming the patient was not a former diabetic, and the patient is asymptomatic. Acute pancreatitis with necrosis of the gland is characterized by focal areas of fat necrosis of varying degree throughout the gland. Depending on the severity and degree of rupture of pancreatic vessels, insignificant to extensive hemorrhage into the parenchyma may be present. Focal areas of pale necrosis may be present in addition to variable areas showing hemorrhage. The term, acute hemorrhagic pancreatic necrosis, is appropriate for those patients with the severist form of acute pancreatitis. Necrotic areas eventually heal, usually with calcification. Pancreatic pseudocysts is one of the complications of acute pancreatitis. Chronic pancreatitis is characterized by irreversible injury to the gland. Systemic manifestations of pancreatitis may be present as evidenced by heart, liver, kidney, and


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other disturbances. Chronic pancreatitis leads to permanent necrotic or fibrotic changes in the gland, replacement of connective tissue, and radiologicallydemonstrable calcification of the gland is usually present. AS with acute pancreatitis, the patient with chronic pancreatitis commonly presents with persistent abdominal pain. Owing to pancreatic exocrine insufficiency, digestive disturbances such as malabsorption and steatorrhea may be present. With the loss of functional beta cells, carbohydrate intolerance and diabetes mellitus appear. Late in the disease, some patients develop pancreatic pseudocysts, and some develop biliary tract or duodenal obstruction, the latter of which requires urgent surgery. The distinction between acute and chronic pancreatitis is in part subjective particularly in some patients with marginal loss of pancreatic function. The causes are often the same, e.g., alcohol abuse or biliary tract disease. Patients with recurrent acute pancreatitis will commonly have very high serum amylase and lipase activities whereas, as expected, patients with recurrent chronic pancreatitis may only show a trivial increase in the serum enzymes owing to the small amount of remaining normal pancreatic tissue.

111. CAUSES OF PANCREATITIS \

The factors which are believed to cause pancreatitis can be divided into three groups: (1) acute and chronic alcoholism, (2) diseases of the biliary tract, and(3) all other causes. Since the pathogenesis of pancreatitis in humans is only partially understood, some of the above causes could also be coincident events or factors in patients with pancreatitis. This is especially the case with the “other causes” category where the relationship is most unclear. With alcohol abuse and biliary tract disease, the relationship is more causal than coincidental since two thirds of patients with pancreatitis have a history of one or the other. The causes of acute pancreatitis are summarized in Table 1. A. Alcoholism There is little doubt that ethanol taken acutely or chronically in excessive amounts can damage the pancreas. The histological changes of the pancreas in chronic alcoholism resemble the fatty degeneration seen in liver cells: hypertrophy and hyperplasia of the endoplasmic reticulum with dilation of the tubular structures, and alterations of the mitochondria.26Other authors also present evidence that chronic alcohol abuse produces demonstrable morphological alterations of the ductal system of the pancreas which may provoke pancreatitis.” Protein plugs, which could also precipitate pancreatitis, have been observed in the pancreatic ducts in patients with alcoholic pancreatitis. The author had a high school friend die of acute hemorrhagic pancreatitis after one heavy drinking bout. A single extensive drinking episode can produce the disease with a fatal outcome. More commonly, attacks of acute pancreatitis occur after 5 to 15 years of continuous heavy drinking.” Alcoholic pancreatitis appears to be a distinct chemical entity with relapses being common, and typically it develops into chronic pancreatitis. Abstention from alcohol reduces the risk of subsequent attacks of pancreatitis or the attacks become milder and less frequent. Patients who persist in abusing their pancreas with alcohol after the first attack of pancreatitis usually continue to have attacks and have a high likelihood of dying from the hemorrhagic form of the disease within 5 to 10 years.’ Alcohol-induced calcific pancreatitis is associated with a bad progn~sis.’~ The mechanism by which alcohol injures the pancreas is not clear. When alcohol is given orally, there is a stimulation of the parietal cells to produce HC1. When either alcohol or HCl comes into contact with the gastric mucosa, the release of secretin occurs. Release of gastrin by the stomach may also be involved which in turn causes further stimulation of the parietal cells. The HC1 inthe duodenum can cause spasms of the sphincter of Oddi, but

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Table 1 BELIEVED CAUSES OF ACUTE PANCREATITIS


I. 2. 3.

4.

5. 6. 7.

8. 9.

10.

I I. 12.

13. 14.

IS. 16. 17. 18. 19.

20. 21.

22.

Chronic alcohol abuse Diseases of biliary tract and gall bladder, Postoperative to Surgery to pancreas and adjacent structures and organs a. Surgery to areas remote from pancreas b. Trauma to abdomen Benign and malignant pancreatic tumors Space occupying tumors near pancreas Blockage of pancreatic ducts a. Tumors or stenosis of ducts b. Tumor or blockage of ampulla of Vater c. Parasitic diseases blocking ducts d. Infectious blockage Obstruction of duodenum Hypercalcemia of various causes Metabolic disorders a. Diabetes mellitus b. Types I and V hyperlipoproteinemia c. Hemochrornatosis Pregnancy and during post-partum period Infectious diseases a. Generalized bacterial infections b. Viral infections Collagen vascular diseases Renal failure and uremia Liver diseases Penetrating peptic ulcer Arteriosclerosis particularly if it affects pancreatic circulation Immunological disorders such as systemic lupus, rheumatoid arthritis, etc. Drugs (See Table 2) Scorpion venom Porphyria Miscellaneous other causes

it may also increase the pressure in the pancreatic duct." In another report, the duodenum was found to be hyperirritable in pancreatitis. The hyperirritable duodenum may have preceded the pancreatitis, and in turn the duodenum may have played a role in obstructing the exocrine flow from the pan~reas.~' Alcohol, of course, also can produce gastritis and duodenitis which may obstruct the exocrine flow from the pancreas. In summary, alcohol is believed to have a direct toxic effect on the pancreas, and alcohol can produce a series of events in the upper gastrointestinal tract which either stimulate pancreatic flow or obstruct the progress of the flow or both."

B. Diseases of the Biliary Tract Biliary tract disease has been reported as present in 5 to 57% of patients with acute or relapsing pancreatitis." At autopsy, gallstones were seen in 57% of patients who had pancreatitis at the time of death vs. gallstones in 18% of patients without pancreatiti~.~ Patients with gallstones are well advised to have a cholecystectomy or treatment with one of the drugs which promote dissolution of cholesterol stones, e.g., urodeoxycholic acid. After surgery or drug treatment for stones, pancreatitis rarely recurs whereas patients with stones are at significant risk to develop pancreatitis.' Stones lodged in the common bile duct are much more likely to precipitate pancreatitis than stones in the gall bladder.33 A stone lodged in the common duct or in the ampulla of Vater may lead to reflux of bile


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into the pancreas which may cause pancreatitis. This view may be oversimplistic in light of the following data in a study, where in patients with pancreatitis, 72% had stones in the gall bladder only, 20% had stones in the common duct, and only 2% had stones lodged in the amp~lla.~‘ Stones in the gall bladder may cause inflammation which could spread to the pancreas via the lymphatics. Another factor is infection. Bile is infected in nearly one half of patients with gall stones, and the infection could spread to the pancreas via the lymphatics or common Possibly reflux of duodenal contents is also the cause of pancreatitis, but this was an extremely infrequent occurrence during radiologic examination after a dose of BaS04.35The ampulla of Vater is quite effective in nearly all patients, and the flow of pancreatic fluid after a meal would also tend to prevent reflux of duodenal contents. Pregnancy is occasionally mentioned as a cause of pancreatitis, yet in a recent report, 18 of 20 pregnant individuals with pancreatitis had gall stones.36These authors concluded that there was no association between pregnancy and pancreatitis, but there was an association between gallstones and pancreatitis.

C. Other Causes “0ther”causes represent about 25% of patients with pancreatitis and often the putative cause is really an assumption or a coincident event. For some causes, e.g., pancreatitis after surgery to the biliary tract and associated structures, it is very likely that the surgery led to the pancreatitis, because pancreatitis is common in these patients. For drug related causes, e.g., the drug propoxyphene, the causality is not proven since so few patients getting the drug get the disease. 1. Surgery The highest risk of postoperative pancreatitis is to patients undergoing surgery to the pancreas, biliary tract, gall bladder, stomach, liver, or other structures close to the pancreas. Pancreatitis appears to be more likely in patients where the pancreas is manipulated during surgery or if afferent or efferent blood vessels of the pancreas are affected in any way. Postoperative pancreatitis is seen less frequently in patients having surgery to regions remote from the pancreas. The pancreatitis may result from the surgery or simply be a coincident event.”

2. Hypercalcemia There are many causes of hypercalcemia (see, for example, review by Lee et al.”), and in some patients with hypercalcemia owing to vitamin D intoxication, hyperparathyroidism, hyperthyroidism, neoplasia, etc., coincident pancreatitis is present. Pancreatitis is much more frequent in patients with hyperparathyroidism than in the general population. In hyperparathyroid storm, i.e., where there is profuse secretion of parathyrin, the incidence of pancreatitis is as high as 30%.38 The mechanism by which hypercalcemia causes pancreatitis might be the following: an increased plasma calcium stimulates the secretion of gastrin which in turn stimulates the secretion of hydrochloric acid by the parietal cells.39Irritation of the duodenum could lead to pancreatitis as described earlier under alcohol-related pancreatitis. This mechanism however has not been proved, and neither has an increase in plasma calcium been shown to cause pancreatitis in an animal model. 3. Drugs A review of possible drug-associated pancreatitis in the English, German, and Japanese literature,@ and a recent review of the English l i t e r a t ~ r e ,summarizes ~~ the information that is available on the above. This information has been further condensed

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Table 2 DRUGS BELIEVED TO CAUSE PANCREATITIS IN SOME PATIENTS'


Category

Definite association

D w Azathiaprine

Chlorthiazide and hydrochlorthiazide

Estrogens alone or in oral contraceptives Valproic acid Furosemide

Sulfonamides

Tetracycline

Probable association

L-Asparaginase

Vitamin D, hyperalimentation. Ca infusion, hemodialysis

Chlorthalidone Corticosteroids

Comment

Pancreatitis in 6% of patients with Crohn's disease who received drug. Also seen in patients with chronic hepatitis, cancer, and those receiving immunosuppressive therapy who all usually received a number of drugs. Infrequent cases of pancreatitis. Pancreatitis seen in 7% of mice 1 to 6 months after start of drug treatment. A rise in serum amylase is common after drug is given. Patients receiving drug tend to have attacks during treatment and no attacks while drug is not given. Pancreatitis seen in children where it is uncommon. Two patients with increase in serum amylase after drug challenge, six other patients with probable association. Two patients with increase in serum amylase after challenge with drug; disappearance of symptoms and normalization of amylase on discontinuance of drug. Pancreatitis associated with fatty degeneration and renal failure believed to be caused by drug. Pancreatitis seen especially in patients given prolonged high-dose therapy. Pancreatitis in 0 to 25% of leukemia patients treated with drug. Many of the patients also received azathiaprine and corticosteroids so association between drug and pancreatitis unclear. All these drugs or treatments tend to raise plasma Ca. There is a possible causal relationship between the hypercalcemia of hyperparathyroidism and pancreatitis and other factors such as multiple myeloma which raise calcium. Report of one patient developing pancreatitis after receiving drug. Pancreatitis seen in over 40 patients receiving corticosteroids. Other drugs or underlying diseases may also have caused the pancreatitis. Some patients were children in which pancreatitis is uncommon.

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Table 2 (continued) DRUGS BELIEVED TO CAUSE PANCREATITIS IN SOME PATIENTS‘


Category

Drug Ethacrinic Acid Phenformin

Possible association

Amphetamines Cholestyramine Warfarin Cyproheptadine Propoxyphene Diazoxide Histamine lndomethacin Isoniazid Mercaptopurine Opiates Rifampicin Salicylates Cimetidine Acetaminophen

Comment Report of one patient developing pancreatitis after receiving drug. Report of six patients with pancreatitis and of other patients with increased serum amylase but not pancreatitis. Other causes of pancreatitis may have been operative, i.e., the underlying diabetes mellitus. Occasional patients receiving drug developed pancreatitis. Association of drug use and pancreatitis unclear and casual relationship usually could not be established. Some patients developed increased serum amylase but not pancreatitis.

’ Adapted from References 38,4042. and is given here in Table 2. The drugs in Table 2 are classified as “definitely associated with”, “probably associated with”, and “possibily associated with acute pancreatitis”. The evidence is strongest for the first group in causing pancreatitis in some individuals. Obviously, some of these individuals may have had underlying disease which predisposed them to developing pancreatitis, and the drug is not responsible. Underlying diseases include biliary tract disease as described earlier, but also include atherosclerosis or any other condition which affects the pancreatic cir~ulation.~’ Another problem with “drug-induced” pancreatitis is that some patients seek help for abdominal pain, are found to have an increased serum and/or urine amylase while receiving a given drug, and are diagnosed as having“pancreatitis”. The patients may have ingested a drug like morphine which causes in some a spasm of the sphincter of Oddi, abdominal discomfort, and a rise in serum and urine amylase. They probably do not have pancreatitis. In any case, drug-induced pancreatitis is often unclear, and the cause of the pancreatitis may be something else or the patient may not have pancreatitis. A recent addition to the list of drugs believed to cause pancreatitis is valproic acid. Five cases of pancreatitis in children have been rep~rted.~’ It is very likely that the drug caused the disease since pancreatitis is rare in children.43 4. Hyperlipemia Abnormally increased serum triglycerides are seen in about one fourth of patients with pancreatiti~.~~ Patients with type I and type V hyperlipoproteinemia who have


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extraordinarily increased serum triglycerides have a much greater incidence of pancreatitis than the rest of the population.'6 It has been proposed that hypertriglyceridemia per se can cause pancreatitis." The proposed mechanism in alcoholics is that alcoholism "in a great many patients - peShaps even a majority - triggers hypertriglyceridemia which in turn triggers acute pancreatiti~".~'There are some problems with this analysis. If it were true, then many more cases of pancreatitis should be seen since increased serum triglycerides is much more common than pancreatitis. Furthermore, many alcoholics have lipid abnormalities either underlying or caused by alcohol, and they do not always develop pancreatitis. Hypertriglyceridemia is probably a coincident event with pancreatitis and not the cause. In some, pancreatitis may lead to an increase in serum triglycerides. In a recent report, it was found that 38 of 117 patients with pancreatitis had type IV hyperlip~proteinemia.~~ They proposed that the increased serum triglyceride concentrations might be owing to an increased synthesis or mobilization and that the increased triglycerides did not directly induce pancreatitis. Yet, increased triglycerides along with other provoking factors, e.g., alcohol, may predispose a patient to pan~reatitis.~~ Free fatty acids are toxic to tissues and the proponents of hypertriglyceridemia-caused pancreatitis say that lipase coming from the pancreas releases free fatty acids from triglycerides and therefore causes pancreatiti~.~'This is most likely incorrect since lipase and triglycerides are always present in plasma; however, lipoprotein lipase and not lipase hydrolyzes triglycerides bound to protein to release free fatty acids. Lipoprotein lipase must be activated (e.g., by heparin) before it will act on protein-bound triglycerides. The term "free fatty acids" is in a way a misnomer. Fatty acids, being insoluble in plasma at pH 7.4, must be bound to protein to remain in solution. Protein-bound fatty acids in plasma are not toxic to the acinar cells of the pancreas. Studies with perfusions of emulsified triglycerides are probably irrelevant as a cause of tissue injury associated with pancreatitis since they are not physi~logical.~' Increases in serum fatty acids were seen in these studies, the significance of which is probably n~nexistent.~' In summary, hypertriglyceridemia is probably not a cause of pancreatitis. It is also unlikely that "it may prove to be possible to reverse or prevent acute pancreatitis directly simply by reducing serum lipid level^".^' Correction of lipid abnormalities has never been advocated in the therapy of pancreatitis and there is no evidence that it would be effective. Lipid abnormalities are difficult to correct with diet and/ or drugs, and achange in serum lipids often takes days to weeks to occur.

IV. PATHOGENIC CASCADE OF ACUTE PANCREATITIS What mechanisms or factors trigger inflammation and autodigestion of the pancreas? The active form of trypsin is clearly one of the major actors in acute pancreatitis, and it has been demonstrated in the pancreatic fluid in patients with pan~reatitis.~'How inactive trypsin (i.e., trypsinogen) in the zymogen granules of the acinar cells is converted to (active) trypsin is still a topic of study. Trypsinogen in the gland can be converted to trypsin in situ by several factors. Bile alone, if it reaches the pancreas, can convert minute amounts of trypsinogen to trypsin which then acts autocatalytically to form more trypsin. Bile is a complex substance; bile acids alone can convert trypsinogen and other substances in bile may do the same. Bacteria in bile can also activate trypsinogen. How bile can reach the pancreas is described above. The injury to pancreatic cells caused by alcohol" may lead to active trypsin, but this remains to be proved. Patients with pancreatitis have been shown to have an increase in the concentration of circulating immune complexes." This means they had activated

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Table 3 PANCREATIC PRO-ENZYMES AND OTHER SUBSTANCES ACTIVATED BY TRYPSIN


Inactive form

Active form

Trypsinogen

Trypsin

Chymotrypsinogen

Chymotrypsin

Proelastase

Elastase

Prophosphoiipase-A

Phospholipase-A

Lecithin (from bile) Kallikrcinogen

Lysolecithin Kallikrein

Lipase

Action of active form on pancreas

’

Produces edema, necrosis, hemorrhage, coagulation of gland Produces edema, necrosis, hemorrhage, coagulation of gland Injury to blood vessels, hemorrhage, infarction In presence of bile acids, causes injury to cell membrane Cytotoxic Liberates bradykinin, kailidin to produce edema, vasodilation, increased vascular permeability, invasion by leukocytes. When released, can produce fat necrosis.

complement present which can injure cell membranes. Cell injury could also follow if secretion of pancreatic fluid is blocked and stasis of fluid occurs in the pancreas. This may be the mechanism of production of pancreatitis by scorpion venom, which stimulates the pancreas. Drugs which are pancreatic secretogogues may produce pancreatitis in a similar way. Free trypsin can activate a number of pro-enzymes as given in Table 3. The active substances listed in Table 3 can injure the gland in various ways. Either the acinar cells are injured, there is injury to blood vessels, or there is injury to connective tissue. Trypsin is important, but the other factors listed in the table can be equally noxious to the gland. Trypsin is used commonly to induce pancreatitis in animals:s however, experimentally produced pancreatitis has the features of liquscation necrosis and extensive leukocyte infiltration, while clinical pancreatitis has the features of coagulation necrosis and usually little or moderate leukocyte infiltration is present. Thus the caveat is always that conclusions drawn from experimentally produced pancreatitis may not apply to the clinical entity. During acute pancreatitis, the enzymes and lysolecithin damage the cells, the interstitial tissues, and the blood vessels. Inflammation and injury, if they cause ischemia, may produce a vicious cycle of further injury and worsening ischemia. Popper et al.,” demonstrated many years ago that if the main pancreatic artery is blocked, pancreatic edema follows. Also, blockage of the pancreaticveins produced edema. Any injury to the blood vessels which affects the afferent or efferent blood supply can produce an edematous pancreas which may lead to pancreatitis. If there is intrapancreatic bleeding, activation of clotting can also activate trypsinogen.” The closing events in acute hemorrhagic pancreatitis are usually complete autolysis and coagulation of the gland with total disruption of the gland’s architecture and hemorrhage into the retroperitoneal space. In the fulminant disease, the fluid shifts into the pancreatic, retroperitoneal, and peritoneal spaces and can produce irreversible shock and death. Acute pancreatitis can have an accelerating downhill course, and death is

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CRC Critical Reviews in Clinical Laboratory Sciences Table 4 PATHOGENIC CASCADE OF ACUTE PANCREATITIS


Initiating event: one or more of following Activation of trypsinogen, injury to gland from alcohol or drugs, bile enters gland, reflux of duodenal contents. infection. activation of complement, action of hypersecretogogues 1

Injury to acinar cell membranes 1

Activation of trypsinogen. kallikreinogen. proelastase. prophospholipase A, chymotrypsinogen. lecithin ( t o form lysolecithin) I Edema, swelling of capsule. pain 1

Enzymatic digestion of gland 1

Ischemia, hemorrhage, fat necrosis 1

Interruption of blood supply t o gland, necrosis. further hemorrhage. leakage of "toxic" substance into blood and/ or peritoneal cavity 1 "Internal burn" t o peritoneum, secondary injury to brain. liver, kidneys. lungs 1

irreversible shock, circulatory collapse, autolysis of gland I Death

common during the first 24 hr in fulminant disease. Olsen has aptly called it an "internal burn" which plays havoc with the body's homeosta~is.~ A proposed pathogenic cascade of acute pancreatitis is given in Table 4.

V. LABORATORY TESTS IN PANCREATITIS A. Primary Tests Which Point to Pancreas Laboratory tests done on serum, urine, whole blood, fluids, etc. are all necessarily secondhand information. They may reflect pathology of the pancreas and they may not. First-hand results, e.g., a biopsy of the gland, may be superior but they involve more risk to the patient, and they are often difficult to evaluate. Data from the laboratory are very important for the diagnosis of pancreatitis, particularly those tests which point to the pancreas, i.e., analytes derived from the gland or analytes which reflect dysfunction of the gland. Tests which point to the pancreas are given in Table 5. One of the reasons why the laboratory findings are so important is that acute pancreatitis presents in many ways, and there are no infallible signs and symptoms which appear in pancreatitis and nothing else. The laboratory data can also be misleading and the diagnosis of pancreatitis cannot be made on laboratory data alone. 1. Serum and Urine Amylase

The most important test is serum amylase. The test is not infallible, yet the recent literature is unanimous in that serum amylase activity must always be measured if pancreatitis is s ~ s p e c t e d . ' *Amylase ~~'~ is a protein with a mol wt of about 50,000; it is filtered by the glomeruli; and it is partly reabsorbed by the tubules. The tissues with highest amylase activity per gram are pancreas and salivary glands. Much lower activities

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Table 5 PRIMARY LABORATORY TESTS WHICH POINT TO PANCREAS Serum and urine amylase Serum lipase Amylase/creatinine clearance ratio Macroamylase Amylase isoenzymes Glucose Trypsin Phospholipase A Benzoyl-Tyrosyl-PABA Pancreatic polypeptide

per gram are present in the ovaries, small and large intestine, and skeletal m ~ s c l e . ’ ~ . ~ ~ Whether amylase is present in liver tissue is u n r e s ~ l v e d . ~There ~ ’ ~ is essentially no measurable amylase activity in any other normal organs of the body. The reported clinical sensitivities and specificities for serum amylase in pancreatitis are quite varied. Amylase certainly does not have the prestige in diagnosing pancreatitis as does creatine kinase-MB in the diagnosis of myocardial infarction.” Ranson described 100 patients with acute pancreatitis, 95 of whom had an increased serum amylase, and in another group of 100 patients with acute abdominal pain secondary to acute cholecystitis, perforated peptic ulcer, intestinal obstruction, o r appendicitis, 95 had a normal serum amy1a~e.I~ Thus, in this report, the sensitivity and specificity of serum amylase were both 95%. In the review by Stefanini et al.,’ the sensitivity of serum amylase was reported as 95% and 84% for two groups of patients of 58 and 93 individuals, respectively, who had pancreatitis. From their summary (Table 2 in Reference 1) of work by others, serum amylase alone had a sensitivity of 45 to 95% in pancreatitis, and a combined group of tests of increased amylase, glucose, and white blood cells had a sensitivity of 41 to 90%. No doubt, methodological problems, diagnostic criteria, and reference ranges that were used affected the reported sensitivities. In another report on 70 patients with pancreatitis, urinary amylase was the most sensitive test (69% sensitivity), serum amylase was next (33%), and serum lipase was the least sensitive (18%).’6 These figures were the sensitivities of the particular tests when they were all done on the same day. It is unclear from this report whether the enzymes were normal throughout the course of the disease for any of the patients or whether some or all tests were abnormal at some point in the course of the disease.56 The specificity of the serum amylase test is adversely affected by two principal causes: (1) the enzyme is found in multiple organs besides the pancreas, and hence diseases of these organ systems will tend to increase serum amylase, and (2) patients may retain amylase in cases of renal failure, i.e., the amylase is not cleared.” Amylase enters the blood compartment at a fairly constant rate, and it is cleared by the kidneys at a fairly constant rate. Serum amylase activities reflect the balance of these competing processes. After an attack of acute pancreatitis, serum and urine amylase typically rise within 2 to 3 hr, and in a mild to moderate case or acute pancreatitis, amylase in both serum and urine return to normal within 10 days.6 An abnormal urine amylase can persist beyond 10 days in a moderate case and is therefore useful in diagnosing pancreatitis late in the disease when serum amylase is normal. An abnormal serum amylase which persists beyond three to four weeks may be caused by a pancreatic pseudocyst3”’ or pancreatic cancer.58 Others” reported that serum amylase is increased within the first 24 hr of a n attack of acute pancreatitis, peaks within the first day, and then returns to normal within 3 to 5


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days. In other literature, serum amylase was found to be frequently, but not invariably, increased within the first day and returned to normal by the third to sixth day.59d4In the presence of extensive pancreatic necrosis, incomplete ductal obstruction, pseudocyst or abscess, the abnormal values may be higher and persist for a longer period of time.I2 Serum amylase may be normal in acute pancreatitis if there is a delay in obtaining blood since the increase in amylase can be transient." Also, in relapsing chronic pancreatitis, so much necrosis of the pancreas may have occurred that there is little acinar tissue left." An increased serum amylase is useful in diagnosing pancreatitis, but the magnitude of the increased activity is unrelated to the severity of the d i ~ e a s e . ~ Indeed, ~ - ~ ' Gullick" has shown the highest serum amylase activities are seen in moderate pancreatitis, and as the severity of the disease increases further with commensurate destruction of the gland, serum amylase may actually fall. Thus a slight increase in the serum amylase activity may reflect either end-stage pancreatitis or mild edematous pancreatitis. There is also no correlation between any of the causes of pancreatitis and the magnitude of the serum amylase activity. Further, it is not possible to use amylase activities (or its isoenzymes)to differentiate pancreatitis from diseases mimicking pancreatitis.' Some have found that very marked increases in serum amylase, i.e., greater than ten times the upper reference limit, are seen more frequently in biliary tract disease than in pan~reatitis.~' Patients with "idiopathic" or alcoholic pancreatitis had amylase activities of two to five times the upper reference limit.72 These authors also state that serum amylase activities tend to be inversely related to the severity of pancreatitis. Lipemia is frequently described as an interferent or "inhibitor" of amylase.'0i73 Hypertriglyceridemia falsely lowers amylase with starch-iodine methods and thus may confuse interpretation. Further, with this method and its variations in the presence or absence of lipemia, diluted sera do not give the expected calculated re~ult.'~ This effect is not seen with dye-bound starch methods7975or the newer enzymatic methods.76 According to literature from duPont for the aca procedure, "lipemia has no effect"(on their enzymatic procedure), but they hedge and add "lipemic sera may contain amylase inhibitor^".^^ Extremely lipemic sera probably interfere with the spectrophotometry and the high absorbances may be in the region of poor spectrophotometric accuracy. Urine amylase continues to be used extensively and is one of the very few enzyme tets on urine which has clinical importance. It also has some problems which may make interpretation difficult: In the presence of kidney disease, amylase may not be cleared and urine amylase is normal despite a marked increase in serum amylase 2. The reference range for urine amylase is very broad7' 3. The test must be done on timed collections of urine; amylase done on a spot urine is usually of no value 4. *Proteinin urine, or if added to urine, will markedly increase the measured amylase activity79 1.

Ascites fluid in acute pancreatitis usually has very high amylase activity. Patients with chronic pancreatitis may have an increased ascites fluid amylase and a normal serum amylase. l 2 Causes other than pancreatitis for abnormal amylase activities in ascites fluid are a leaking pancreatic pseudocyst, pancreatic ductal rupture, pancreatic cancer, tumors in the abdomen that secrete amylase, and perforation of a hollow viscus." Occasionally, patients with pancreatitis have pleural effusionswhich often have high amylase activities. This is not diagnostic for pancreatitis. Some patients with lung tumors can have a pleural effusion or serum with very high amylase activities.@'"


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2. Serum Lipase Serum lipase is a test that should be performed more frequently in patients with suspected pancreatitis. Unfortunately, the best substrate is an emulsion of, for example, corn or olive oil in water, and the substrate is hard to prepare reproducibly. Production of the emulsion is tricky, and the measured activity of the enzyme is related to how finely the oil is dispersed.82The test has a reputation of poor reproducibility, and the older methods were tedious and took 24 hr to ~omplete.'~ Lipase has also been given a bad name since some methods that use solubilized substrates, such as tributyrin, triacetin, or methyl butyrate, which purportedly measure lipase, do not measure lipase at all, but rather measure esterases coming from e.g., the liver. These esterases are aliesterase, lipoprotein lipase, aryl ester hydrolase, and other esterases. It has been shown that only in those lipase methods which employ an emulsified vegetable oil as substrate is there a correlation with pan~reatitis.'~ Pancreatic lipase only acts at the interface of an oil-inwater emulsion to hydrolyze the esters to fatty acids and glycerol.82 The lipase in normal serum is believed to have different properties than the enzyme coming from the inflamed pan~reas.'~This suggests that serum lipase in healthy persons is not entirely of pancreatic origin. Lipase activity can be demonstrated in the pancreas, intestinal mucosa, stomach, leukocytes, and adipose tissue.''-'' There is no lipase in the salivary glands which is an advantage when parotitis must be differentiated from pancreatitis. An increase in serum lipase tends to parallel an increase in the serum amylase activity ~ ~ some ~ ' ~ ' ~instances, serum lipase is increased before in acute p a n ~ r e a t i t i s . ' " ~ ~In amylase, and in some patients with pancreatitis, an abnormal lipase persists for a longer time than an abnormal a m y l a ~ e . ' ~In' ~the ~ experience of Lifton, et a1.,90 in patients on admission, a 5-min turbidimetric method for lipase gave abnormal results in 63% of patients with pancreatitis as compared to 73% of patients with an increased amylase, and 83% of patients with an increase in either enzyme. There were two patients whose serum lipase went up before amylase and all patients had either or both enzymes increased above normal during the course of their disease.90 Contrary to the older literature, lipase is absent from urine.91The measurement of lipase in fluid from the duodenum or in ascites fluid in pancreatitis has never received much probably owing to the unfavorable reputation of the lipase test and the ease of performing amylase assays on the same materials.

3. Amylase1 Creatinine Clearance Ratio The ratio of the clearance of amylase to creatinine (X 100) in normal individuals is 1% to 4% regardless of the method used to measure serum and urine a m y l a ~ e . ~ In~acute -~~ pancreatitis, there is an increase in this ratio to about 6%. A finding of an increased ratio is very sensitive for pancreatitis but not very specific. The cause of the increased ratio appears to be an inhibition of the tubular reabsorption of amylase." In patients with no compromise of kidney function and with pancreatitis, the creatinine clearance is usually unchanged. Other proteins such as /3-2-microglobulins are also not reabsorbed to the same extent as normal in the presence of pancreatitis. This is the cause of the nonspecificity of the test. In other acute states like diabetic ketoacidosis,lOOsevere burns,'" severe renal insufficiency,lo2duodenal perf~ration,''~ and pancreatic cancer,"' an increase in the ratio is also seen. Duerr et al.Io4also found the clearance ratio not to be very sensitive to pancreatitis. They found in 29 out of 79 patients with proven acute pancreatitis that the clearance ratio was not increased during the acute phase of the illness. Others found the ratio to be increased in pregnant women with hyperemesis, and in those with toxemia with epigastric pain."' They concluded that the test had poor specificity, but it could still be used as a screen for pancreatitis in pregnant individuals.


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In patients after surgery, the test appears to have very little value in detecting pancreatitis. Of 77 patients undergoing abdominal surgery, 36 had an increased and abnormal ratio whereas pancreatitis was present in only 8.Io6 In the same study, of 60 other patients with nonabdominal surgery, 23, had an abnormal ratio; none had pancreatitis. A similar finding was made by others in patients examined postoperatively. They found an abnormal ratio 24 hr after surgery to the stomach or gallbladder, but not after surgery to sites remote from the abdominal cavity. None of the 12 patients had pan~reatitis."~ The early enthusiasm for the ratio of the clearance of amylase to creatinine in the diagnosis of pancreatitis has waned. It will probably be used less and less in the future. 4. Macroamylasemia An increased serum amylase in the presence of a normal or low urine amylase suggests the presence of macroamylase in serum. Amylase may be bound to IgG'" or IgA"', and with a mol wt of about 20 million, it is too large a molecule to be filtered. Most individuals with an increased serum amylase owing to macroamylasemia do not have pancreatitis*"O'lll It is not diagnostic of pancreatitis; however, a report on one patient with pancreatitis stated that macroamylasemia was also present." Whether the macroamylase comes from the pancreas is ~ n k n o w n . ' ~ ' ' ' ' ~ Hydroxyethylstarch, -'~~ which has been used as a plasma substitute, regularly induces macroamylasemia and hyperamylasemia."51"6 One study reported the synthesis of macroamylase by combining salivary or pancreatic amylase with human IgG. The complex proved to be very stable and only partially dissociable at pH 3.5. Small amounts of macroamylase also formed when salivary or pancreatic amylase were added to normal serum.117 5. Amylase Zsoenzymes

Isoenzymes of amylase can be demonstrated in serum, and what is seen is method dependent."* Six isoenzymes have been found using cellulose acetate; three salivary (S-1 to S-3) and three pancreatic (P-1 to P-3) isoenzymes."' The isoenzymes that are seenvary with the individual, i.e., there appears to be genetic control of the isoenzymes. The condition of the specimen also determines the isoenzyme pattern that is observed."' Another report on normal subjects described the P-3 isoenzyme of amylase in 95% of specimens and the P-1 isoenzyme in only 2%. The S-1 form was seen in 95% of cases and the S-2 and S-3 appeared less frequently.'2' Amylase activity can always be demonstrated in the serum of healthy persons. The primary isoenzyme of amylase in serum is salivary, approximately 65% of the total activity, and the rest is p a n ~ r e a t i c . ' ~ ~ ' ' ~ ~ In one report, patients with mumps had an increase in the salivary isoenzymes and patients with pancreatitis had increases in the pancreatic isoenzymes of a m y 1 a ~ e . IAn ~~ increase in the pancreatic isoenzymes was pathognomonic for abdominal disease but not necessarily pan~reatitis."~ Further, an increase in the salivary isoenzymes did not always mean salivary gland involvement, i.e., identification of the salivary isoenzymes did not unambiguously identify the tissue of origin. Yet, the interesting result of this study was that an increase in the salivary isoenzymes in the absence of disease of the salivary glands pointed to a possible amylase production by a neoplasm.'24 They saw patients with ovarian carcinoma with increased salivary amylase isoenzymes. Three other case reports in the literature describe patients with lung tumors who had increased salivary-type amylase in serum.801*'*12s Perhaps this isoenzyme is a tumor marker in a few individuals. 6. Glucose Disturbances of carbohydrate metabolism are common in pancreatitis.'26 Both serum insulin and glucagon are increased in pancreatitis," and the glycemia that is observed


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reflects the relative balance of these two hormones. Glucagon was sharply increased in experimental pancreatitisZ5and is probably increased in many patients with pancreatitis if they have hyperglycemia. Olsen observed hyperglycemia in 14 of 95 patients with pancreatitis and glycosuria in 16 of 74 patients with pancreatitis, none of whom were diabetic. Persistent hyperglycemia after recovery from pancreatitis is strong evidence of loss of a large percentage of functional pancreatic tissue. Patients with chronic pancreatitis may have chronic hyperglycemia, and a recent report stated that these nondiabetic patients may develop the retinal lesions and retinal vascular microaneurisms seen in diabetic indi~iduals.''~ Some diabetic individuals with loss of control of glycemia or in ketoacidosis have, along with the hyperglycemia, an increase in a m y l a ~ e . ' ~ ~Whether ''~ they have pancreatitis is questionable, since with correction of the hyperglycemia there is usually a fall in serum amylase. Lipase has been observed to be normal in these patient^,"^"^^ and the increase in serum amylase may not be owing to inflammation of the pancreas. 7. Trypsin Trypsin enters the blood during acute pancreatitis, however, the measurement of plasma or serum trypsin has been plagued by technical problems. Only recently are studies appearing on serum trypsin where the test appears to be helpful in acute pancreatitis. Plasma contains antiproteases such as thrombin, plasmin, alpha-I antitrypsin, which all act to bind trypsin and render it enzymatically inactive.* Trypsin in serum must be measured as a protein rather than as an enzyme. There are reports in the recent literature which recommend measuring trypsin and others who consider the test useless. These studies are summarized here. In one study, the cohorts were normal persons, patients with chronic renal failure, mumps, acute pancreatitis, cancer of the pancreas, and chronic pan~reatitis.'~' Immunoreactive trypsin (IRT) was measured by radio-immunoassay. The patients with acute pancreatitis and chronic renal failure had the highest IRT; patients with mumps, cancer of the pancreas, and the normal individuals had about the same values; patients with chronic pancreatitis had the lowest values." In this report, some patients with acute pancreatitis could not be distingished from normal persons using IRT, however, serum amylase done on the same specimens gave a better separation between these two groups. Why IRT is increased significantly in chronic renal failure is not c1ear.lm Another report describes the measurement of serum amylase, isoamylases, and IRT in 103 patients with "pancreatic disease" and in 29 control^.'^' Most patients with pancreatic disease had an increase in both pancreatic isoamylase and IRT as well as total amylase. There was a strong correlation between pancreatic isoamylase and IRT, yet there was a great deal of overlap of the values between the patients and the controls. Patients with acute pancreatitis had the highest IRT, pancreatic isoamylase, and total amylase. From their data, no additional diagnostic sensitivity or specificity can be claimed for IRT or pancreatic isoamylase as serum amylase gave just as good a separation between the two groups as did the other tests. It did not appear worthwhile to do IRT and isoamylases in addition to amylase based on their data.I3* Other studies using IRT involved patients with pancreatic adenocarcinoma and chronic pancreatitis. IRT was not helpful in distinguishing between the two diseases, but the test may have some value in the diagnosis of ~teatorrhea."~ Tryptic-like activity in serum was described in another study in 45 patients with pancreatitis and in 61 contr01s.I~~ Test results were higher in pancreatitis, however there was a lot of overlap between populations. None of the above studies make a good case for measuring IRT in serum for the diagnosis of pancreatitis. A study by Koop et al.134reports a large amount analytical

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variability in a radio-immunoassay kit method for IRT. They saw coefficients of variation of 26 to 44%, and not surprisingly, they could not distinguish between patients with chronic relapsing pancreatitis and normal controls with this test. They report the test to be useless in this situation. IRT has been demonstrated in the pancreatic fluid of patients obtained during the course of endoscopic e ~ a m i n a t i o nPatients .~~ with cancer of the pancreas and others with chronic pancreatitis were examined in this way. The former group had decreased concentrations of IRT while the latter had increased or normal IRT concentrations in pancreatic fluid. Lactoferrin was also measured in pancreatic fluid by these workers, and they claim that with this test, patients with cancer of the pancreas and chronic pancreatitis can be ~ e p a r a t e dOwing . ~ ~ to the difficulty in obtaining a specimen and doing these tests, they are not likely to become widely used. In related work, protease-antiprotease complexes have been demonstrated in ascites fluid in patients with acute pan~reatitis;'~' and in a rat model of pancreatitis, proteolytic enzymes were shown to be present in ascites fluids.136Finally, a pancreatic secretory trypsin inhibitor has been found in the serum of patients with pan~reatitis.'~'The inhibitor presumably prevents activation of trypsinogen in the pancreatic duct and was believed to come from the pancreas. The test for the inhibitor was claimed to be superior to serum amylase in diagnosing edematous pancreatitis while amylase was better in diagnosing hemorrhagic pancreatitis. Another study appears to contradict this in stating that tests for trypsin inhibitor(s) are of no value in acute pan~reatitis.'~' 8. Phospholipase-A Phospholipase-A probably plays a role in the pathogenesis of pancreatitis, and it is believed to injure acinar cell membranes. It comes from the pancreas and enters the blood in acute pancreatitis. It has been measured in experimental pancreatitis in a pancreatic exudate; the values paralleled amy1a~e.I'~ In humans, the enzyme was higher in ascites fluid in patients with pancreatitis as compared to patients with cirrhosis.'a A recent report of the measurement of phospholipase-A-2 in serum states that the enzyme is present in significantly higher activities in patients with hemorrhagic pancreatitis as compared to the milder edematous form of the disease.I4' This test probably deserves more attention although the technical problems in performing the test look formidable. 9. Benzoyl- Tvrosyl-Para-Amino Benzoic Acid (BT-PA BA) Chymotrypsin cleaves BT-PABA to PABA and other products; the PABA is absorbed in the small intestine and excreted in urine. This drug after being given orally (Chymex (R), Adria Laboratories) can be used to assess exocrine pancreatic function." Excretion of PABA is significantly reduced in patients with chronic pancreatitis, although in one study there was much overlap with the findings in patients and in normal controls.'42 It is a test which is easy to perform, is not invasive, and the determination of PABA in urine by a diazotization technique is simple. The test is of limited value in patients with diseases of the intestinal mucosa which may result in poor absorption of the drug, in patients with liver disease which limits conjugation (primarily with glucuronic acid), and in patients with kidney disease where excretion may be incomplete. Further, the test is only of value in patients with extensive loss of exocrine pancreatic function. With as little as 10 to 15% functional exocrine tissue, the excretion of PABA can be normal. This drug is under current active study.

B. Secondary Tests Which Point to Other Pathologies Pancreatitis often develops into a multisystem disease; secondary injury to the kidneys, liver, lungs, etc., plus plasma volume shifts are reflected in certain laboratory findings. These tests are summarized in Table 6.

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Table 6 SECONDARY LABORATORY TESTS WHICH POINT TO OTHER PATHOLOGIES Electrolytes. Na', K', Cl-, HCO; pH, PCO2, PO1 Creatinine Urea Calcium Magnesium Trig1ycerides Liver Enzymes Bilirubin Coagulation factors Hemoglobin Hematocrit White Blood Cell Count

I . Electrolytes, p H , PCOZ and PO2 The patient acutely ill with pancreatitis is rarely fed by mouth, and often vomiting and gastrointestinal disturbances, e.g., diarrhea are present. Significant electrolyte and acidbase disturbances can occur, and with fluid and electrolyte therapy, monitoring of serum ', C1-, HCO;, pH, PCOZ, and PO2 are important. Vomiting can lead to Nd, K hypochloremic alkalosis with attendant hyp~kalemia.~ Dehydration owing to fluid loss to the peritoneal cavity must be dealt with, and the above two conditions require the fairly frequent performance of these tests. 2. Creatinine and Urea Hypotension is seen commonly in late pancreatitis. The kidneys are vulnerable to hypotension which may lead to acute tubular necrosis and abnormalities in these renal function tests." Cases have also been described of patients with pancreatitis who develop fibrin deposits in the glomeruli. Acute renal failure is not common in pancreatitis, however, it can be detected with the above and other tests.143 Serum creatinine and urea are often moderately increased owing to dehydration, hypotension, and the resulting inadequate perfusion of the kidneys. Prerenal azotemia of this cause rarely results in urea nitrogen concentrations of above 50 mg/dQ.' Urea is usually increased to a greater extent owing to the negative nitrogen balance of patients with pancreatitis. Starvation, fever, and protein losses contribute to the negative nitrogen balance.

3. Calcium and Magnesium Hypocalcemia is seen in many patients with acute pancreatitis accompanied occasionally by hypomagnesemia. A low serum magnesium often makes it difficult to reestablish a normal calcium by intravenous calcium salts." Why serum calcium is low in pancreatitis is unknown. A very low calcium, i.e., less than 7 mg/dQ(3.5mEq/P), carries a bad prognosis. A low calcium has been believed to be owing to the sequestration of calcium by the fatty acids in the peritoneum. Fatty acids are produced by the action of the lipolytic enzymes coming from the inflammed pancreas. This explanation of a low serum calcium is open to question. First, the amount of calcium so sequestered is not very great, and secondly, the body has tremendous amounts of easily-mobilized calcium in the bones. It may be that patients with pancreatitis develop functional hypoparathyroidism in that parathyrin is either not secreted in adequate amounts to mobilize calcium or that the parathyrin is ineffective owing to competition with factor(s) coming from the inflammed pancreas. Recently published clinical evidence tends to support this view.'44

218


Table 7 LIVER FUNCTION TESTS IN PANCREATITIS AND BILIARY TRACT DISEASE


Observed values in cases of Test

Acute Alcoholic pancreatitis

Chronic alcoholic panereatitis

0.1-9 6 of 21

0.1-27 19 of 47

I .O-4.8

2-17

1-47

2-12

Bilirubin, mg/dP Abnormal/ total patients Alkaline phosphatase (Normal to 3 U / Q ) Abnormal/ total patients

9 of 20

Biliary tract disease

70f9

I9 of 47

9 of 10

Aspartate Transaminase (Normal to 40 U/P) Abnormal/ total patients

26-495

16-928

72-246

15 of 19

35 of 46

6 of 6

Alanine transaminase (Normal to 35 U/Q) Abnormal/ total patients

9-169

2-198

40-306

10 of 19

23 of 47

7of7

Adapted from Reference 4.

A low serum protein and albumin are also present in some patients with pancreatitis, and this may be another reason why serum calcium is low. It is possible, however, to have a normal albumin and a significantly decreased calcium in pancreatitis.25 4. Triglycerides Triglycerides in serum can be very high in pancreatitis, and several mechanisms have been proposed: 1. The patient had an underlying hyperlipidemia which was exacerbated by the disease 2. The body is unable to clear circulating lipids owing to a “toxin” coming from the pancreas 3. Alcohol disturbs lipid metabolism.

5. Enzymes and Bilirubin Serum alkaline phosphatase, transaminases, leucine aminopeptidase, gammaglutamyl transpeptidase, and bilirubin are increased in some patients owing either to obstruction of the distal common bile duct by an edematous pancreas or by associated liver disease, e.g., alcoholic hepatitis.I2 One fifth to one third of patients with pancreatitis are also jaundiced. The causes of jaundice are varied, but commonly they involve degenerative changes of the pancreas and biliary ducts. Bilirubin up to 15 mg/dQhas been seen in acute severe pancreatitis in cases with a common duct stone, pancreatic abscess or pseudocyst, or cancer of the head of the pancreas. An increased bilirubin may indicate coincident liver disease. A moderate increase in bilirubin and a rapid fall back to normal usually means that the pancreatitis is of the mild edematous form with or without a stone in the common duct.6 Table 7, adapted from Olsen; gives some indication of the

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frequency and degree of liver involvement in patients with pancreatitis. The tests are of very limited diagnostic value, however, they do give an indication of the severity of pancreatitis and the degree of coexistent liver d i ~ e a s e . ~

5. Coagulation Factors Coagulation abnormalities may be present in patients with pancreatitis. The prothrombin time may be mildly to moderately increased, and there may be a decrease in the number of platelet^.^ Of patients with severe acute pancreatitis, 10 to 15% had blood in the stool which may reflect injury to the duodenum or gastric mucosa adjacent to the inflammed pancreas or may simply be a result of hypocoagulability.I6 Retroperitoneal or intraperitoneal hemorrhage is a very grave consequence of acute pancreatitis and must be managed surgically at once if the patient is to survive.16 A patient who is unresponsive to vitamin K therapy probably has significant liver damage. Sd&e patients with pancreatitis become hypercoagulable and their state resembles disseminated intravascular coagulation. They have microthrombi in the lungs and kidneys.I6 Ranson reported increases in fibrinogen and platelets early in acute pan~reatitis.'~ Circulating enzymes or toxic factors coming from the pancreas may play a role in the pathogenesis of the coagulation changes that are seen. The changes in clotting factors is one of the systemic manifestations of pancreatitis. Whether tissue injury produces clotting abnormalities or vice versa is ~nc1ear.l~ 6. Hemat ological Factors Hemoglobin and hematocrit are often increased in the early stages of pancreatitis owing to fluid shifts out of the vascular compartment and hemoconcentration. In the late stage of the serious disease, hemoglobin, and hematocrit may be reduced and continue to decline owing to bleeding into the area surrounding the pancreas.' The white cell count may be decreased; however, if an abscess is present, it is nearly always increased. The erythrocyte sedimentation rate is nearly always increased in the acute disease.

7. Miscellaneous Laboratory Studies Pancreatic peptide, one of the recently discovered hormones in the pancreas, may be of value in diagnosing chronic pancreatitis. After a challenge by a meal, normal individuals had an increase in serum pancreatic polypeptide while some of the patients with chronic pancreatitis did not show a similar increase. There was considerable overlap in the pancreatic polypeptide response between the normals and patients. There was also no correlation between pancreatic polypeptide concentrations and the exocrine function of the pan~reas.'~' This test needs further study. Another test, serum ribonuclease may be of some value; however, it was not very effective in distinguishing normals or patients with ' ~similar ~ finding was made for serum ga~trin.'~' Tests on acute or chronic p a n ~ r e a t i t i s .A ascites fluid besides amylase and trypsin include m e t h e m a l b ~ r n i nand ' ~ ~ a substance with "prostaglandin-like" activity.'49 The significance of these findings remains to be determined.

VI. OTHER DIAGNOSTIC TOOLS Other diagnostic techniques and tools have been reviewed elsewhere,61''1'2~'6 and will be summarized here. A. Symptoms and Physical Findings Nearly all patients with acute pancreatitis present with severe abdominal pain. The pain may spread over the entire abdomen, the dorsal and lumbar regions of the back, and the lower anterior thorax. The pain has been described as steady, unrelenting, and

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Table 8 PHYSICAL FINDINGS IN ACUTE PANCREATITIS'


A.

B.

C.

General Appearance Early disease: flushed face, restlessness, considerable discomfort and I. complaints, warm extremities. Late disease: pallor, sweating. apathy. reluctance to move or breathe. cold 2. and clammy extremities Abdomen Early disease: tenderness. rebound tenderness, muscle spasm, board-like I. rigidity as seen in perforation of hollow viscus usually absent. Enlarged pancreas may not be palpable. Late disease: Distension, ileus, ascites, accumulation of gas. decreased 2. bowel sounds. absence of peristalsis, dullness to percussion Other Physical Findings in Early and Late Disease Fever of + 2 O + 3 O , fever of + 3 O may be owing to abscess. Chills I. 2. Pulse of above 100. increased rate of respiration Dyspnea, orthopnea in severe attack 3. 4. Pleural effusions, pulmonary atelectasis 5. Cutaneous signs (Cullen's sign, Turner's sign) owing to subcutaneous changes caused (possibly) by proteolytic and other enzymes seen on legs, hands, forearms. face, abdomen 6. lncreased or decreased blood pressure. Very low blood pressure in patients with shock, hypovolemia. circulatory collapse 7. Scleral icterus '

' Not all findings present in all patients. penetrating. The onset of pain may be sudden and severe or develop slowly, peak at excruciating intensity, and subside slowly. Pain tends to persist for hours to days.6 The physical findings in acute pancreatitis depend on the severity of the attack, when the patient seeks help, the presence of associated or underlying disease, the use of analgesics, previous attacks, and other factors depending in part on the age of the patient. The commonest physical findings are given in Table 8.

B. Physical Methods in the Diagnosis of Pancreatitis Computerized tomography, ultrasonography, radioisotopic scanning, and modern roentgenography have aided greatly in the diagnosis of pancreatitis. All of these tools are discussed in considerable detail e l s e ~ h e r e . ' ~ 'Ultrasound ~'~~~ and computerized tomography have become the best methods short of surgery to diagnose pancreatic pseudocysts, the presences of ascites fluid, and edematous pancreatitis.'" Arteriography and barium studies are the older tools, and both are less sensitive and specific than the newer physical methods described above. For calcific pancreatitis, the diagnosis is still made readily by X-ray examination. C. Surgery Pancreatitis can be diagnosed or excluded by nonoperative methods in most patients. Nevertheless, there is a small group of patients where the diagnosis or exclusion of pancreatitis can be made only after laparotomy. Gangrenous cholecystitis, mesentery artery infarction, perforated hollow viscus, and strangled or obstructed bowel can be diagnosed or excluded at this time.Ig The patient who is acutely ill with pancreatitis is a very poor surgical risk, and the mortality after laparotomy is much higher as compared to patients treated more con~ervatively.'~ Yet for some with the conditions other than pancreatitis listed above, immediate surgery is necessary to save the life of the patient.

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Table 9 DISEASES WHICH MIMIC PANCREATITIS‘ Possible differentiating findings


Condition

Stone in common bile duct or “gallstone colic” Perforation of hollow viscus, e.g.. perforated duodenal ulcer Strangled bowel or bowel obstruction Acute myocardial infarction Dissecting or ruptured aneurysm Infarction of mesenteric artery

Benign paroxysmal peritonitis (Familial Mediterranean fever) Acute appendicitis Ruptured spleen Liver abscess Alcoholic hepatitis Acute porphyria Perinephric abscess

Attack usually of short duration, i.e., I to 6 hr. Serum amylase 1OX upper normal Sudden acute onset, shock, signs of peritonitis, history of ulcer Exaggerated bowel sounds, abdomen less tender than in pancreatitis ECG,abnormal cardiac enzymes (CK,AST, LD), cardiac arrhythmias, normal amylase Usually normal pancreatic enzymes Increase in serum amylase usually less than in pancreatitis, history of abdominal angina Usually normal pancreatic enzymes Pancreatic enzymes usually normal Pancreatic enzymes usually normal Pancreatic enzymes usually normal Pancreatic enzymes usually normal Pancreatic enzymes usually normal Pancreatic enzymes usually normal

’ Adapted from References 6 and 23. The diseases which mimic pancreatitis and where surgery is often required are listed in Table 9. Obviously, specific therapy cannot begin until after the correct diagnosis has been made.

D. Stimulation Tests Stimulation tests are rarely performed in patients with pancreatitis, since stimulation is contrary to the usual therapy of trying to remove all stimuli to pancreatic secretion. Secretin stimulation tests have been used in pancreatitis, especially chronic pan~reatitis.”~”~ Patients who had pancreatic insufficiencyshowed the smallest increase in serum amylase after a dose of secretin, normals had intermediate values, and patients with “early chronic pancreatitis” showed the largest increases in serum amylase. They claimed their evocative test to be superior for diagnosing early chronic pancreatitis as compared to a test using duodenal intubation and assaying the aspirated fluids for amylase and bi~arbonate.”~

VII. COMPLICATIONS AND MORTALITY IN ACUTE PANCREATITIS As discussed earlier, acute pancreatitis exhibits both local and systemic effects. Severe and often life-threatening complications can follow an attack, and most, if not all, of the important organ systems of the body are involved as listed in Table 10. The mortality of pancreatitis depends on the seventy of the disease, and it is much higher in cases with hemorrhage and necrosis as compared to patients with edematous pancreatitis. In the edematous disease, the mortality ranges between 5%4 to as high as 40%.’” In a summary of reports on 247 patients with acute hemorrhagic and necrotic

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CRC Critical Reviews in Clinical Loboratory Sciences


Table 10 FREQUENTLY SEEN COMPLICATIONS OF ACUTE PANCREATITIS' Pancreas: autolysis of gland, loss of exocrine fhnction, loss of endocrine function, diabetes mellitus. malabsorption syndrome, pseudocysts, abscesses Cardiovascular: hypotension: shock, circulatory collapse, loss of blood volume, tachycardia, decreased cardiac output, hypoperfusion of organs, ECG changes, increase in peripheral resistance Respiratory: tachypnea. cyanosis, hypoxemia, pulmonary infiltration, atelectasis, pleural effusions, respiratory failure Renal: acute renal failure, fibrin deposits in glomeruli, acute tubular necrosis Hepatic: hepatic dysfunction, biliary obstruction. jaundice, necrosis of hepatic parenchyma Hematological: lntravascular thrombosis in pancreas and other organs, disseminated intravascular coagulation, profound anemia owing to blood loss Central nervous system: neuropsychiatric complications, loss of orientation, hallucinations, coma, psychosis Gastointestinal: ileus, vomiting, diarrhea General systemic: infection, septicemia, electrolyte and acid-base disturbances Other: retinal abnormalities

' Adapted from References 13 and 127.

Table 11 INDICATIONS OF A POOR PROGNOSIS IN ACUTE PANCREATITIS' A.

B.

When patient is first seen I. White cell count over 16,000 cells/uP Serum glucose over 200 mg/dL 2. Lactate dehydrogenase over two-times normal 3. Aspartate transaminase over five-times normal 4. 5. Age over 55 years Chronicalcohol abuse of more than 10 yearsduration 6. 7. Previous admissions for pancreatitis After 24 hr of hospitalization 1. Drop in hematocrit. serum calcium Rise in serum urea, creatinine 2. 3. PO2 of less than 60 mm 4. Base deficit of greater than 4 mEq/P

' Adapted

from References I I and 13.

pancreatitis, the average mortality was 42R.I' In cases of total necrosis of the gland, the disease is nearly always fatal." Postoperative pancreatitis also has a bad prognosis and the mortality averages 42%." Prognosis can be predicted from the factors listed inTable 11. Most of the predictors are laboratory derived.

VIII. POSSIBLE TOXIC SUBSTANCE(S) COMING FROM INFLAMED PANCREAS The systemic nature of acute pancreatitis has been described earlier. Many students of pancreatitis believe that a toxic material is liberated by the inflamed pancreas which

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Table 12 POSSIBLE TOXIC SUBSTANCE(S) COMING FROM INFLAMED OR NECROTIC PANCREAS’ Ascites fluid protein Bradykinin Chymotrypsin Factor causing increased vascular permeability Hemochromagen Histamine Histamine-releasing factor Hypotensive agent

Kallikrein Kinins Lipolytic agent Methemalbumin Phospholipase-A Prostaglandins Trypsin Vasodilating factor

* Adapted from References 17-19.

157-160.

causes the changes seen elsewhere in the body. The changes seen in the liver, kidneys, brain, lungs, etc. are different from what is seen in patients with hypotension and fluid loss a10ne.I~ The strongest evidence for a circulating toxin comes from the experience with peritoneal lavage as a treatment for acute pan~reatitis.’~’’~ During lavage, what is presumed is that a toxic substance is removed from the peritoneal cavity and this accounts for the better survival of patients treated in this way. One report described the effect of a pancreatic exudate to produce systemic hypotension, release of histamine, and increased vascular permeability in an animal There is considerable research underway in this area to try to identify the toxic material. If this toxic material were known, possible better therapeutic measures could be instituted. A list of possible factors is given in Table 12.157-160

ACKNOWLEDGMENT I would like to thank Mrs. Cindy Berner for her expert secretarial assistance.

REFERENCES I . Stefanini, P., Errnini, M., and Carboni, M., Diagnosis and management of acute pancreatitis, Am. J. Surg., 110, 866. 1965. 2. Kowlessar, 0. D., Diseases of the pancreas, in Cecil-Loeb Texrbook of Medicine, 13th cd., W. B. Saunders, Philadelphia, 1971, 1312. 3. Gambill, E. E., Puncreuriris. C. V. Mosby, St. Louis, 1973. 4. Olsen, H., Pancreatitis. A prospective clinical evaluation of 100 cases and review of the literature, Am. J. Dig. Dis., 19, 1077, 1974. 5. Carey, L., Acute and chronic pancreatitis. Surg. Clin. Norrh Am.. 55, 325, 1975. 6. Gambill, E. A., Pancreatitis and the acute abdomen: Clinical and laboratory approaches to diagnosis, in Gustroinresrinul Emergencies. Clearfield, H . R. and Dinoso, V. P., Jr., Eds., Grune & Stratton, New York, 1976, 231. 7. Kowlessar, 0. D., Pathogenesis of pancreatitis, in Gusrrointesrinul Emergencies, Clearfield, H. R. and Dinoso, V. P., Jr., Eds., Grune & Stratton, New York, 1976, 223. 8. Gowenlock, A. H., Diseases of the alimentary tract, in The Principles and Prucrice ofDiugnosric Enzymology, Wilkinson, J. H., Ed., Edward Arnold Publ., Chicago, 1976, chap. 11. 9. Salt, W. B., I1 and Schenker, S., Amylase - Its clinical significance: a review of the literature, Medicine. 55, 269, 1976. 10. Awanitakis, C., Cooke, A. R., and Greenberger, N. J., Laboratory aids in the diagnosis of pancrcatitis, Med. Clin. Norrh Am., 62, 107, 1978.


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