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Laboratory Diagnosis of Acute Pancreatitis and Pancreatic Adenocarcinoma
Symposium on Clinical Laboratory Medicine
Laboratory Diagnosis of Acute Pancreatitis and Pancreatic Adenocarcinoma Larry M. Cornelius, D.V.M., Ph.D.*
ACUTE PANCREATITIS Inflammatory disorders of the pancreas may be either acute or chronic. In general, the etiology is poorly understood, and indeed, it is likely that a variety of causes may initiate a series of pathophysiologic events which culminate in acute or chronic pancreatitis. Just as the etiologies and pathophysiology have not been well defined, the clinical signs also may be misinterpreted due to their similarity to signs caused by other more common disorders. The purpose of this discussion is to familiarize the practicing veterinarian with the various laboratory procedures thought to be most useful in the diagnosis and management of acute pancreatitis. Emphasis will be given to their proper interpretation. Laboratory Findings As has been previously reported, acute pancreatitis is a disease of extreme variability.U This is probably because the inflammatory process may be limited to a fairly mild interstitial edema or may be a fulminant hemorrhagic, necrotic inflammation. Ability to diagnose acute pancreatitis by laboratory means may depend upon the type and severity of inflammation present and the duration of the process. Acute pancreatitis should be most highly suspected in the obese, sedentary, middle-aged to older house pet which consumes a high fat diet. Episodes of anorexia, vomiting, and abdominal pain in this type animal should always alert the clinician to the possibility of acute pancreatitis. Although the disorder is usually self-limiting, diagnostic procedures should not be delayed since the disease can sometimes progress rapidly into shock and death. *Associate Professor, Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, Georgia Veterinary Clinics of North America-Vol. 6, No.4, November 1976
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It should be emphasized that no single laboratory test is specific enough to be diagnostic of acute pancreatitis. In dealing with any complicated internal medical disorder, the clinician must always evaluate ancillary tests in light of his clinical observations. This is certainly true when considering a diagnosis of acute pancreatitis.
Serum Amylase and Lipase Serum amylase and lipase are still the most heavily relied upon tests to help confirm or refute the presence of acute pancreatic inflammation. These enzymes are produced in the pancreatic acinar cells and are normally secreted into the pancreatic ductular system for transport to the duodenum. Inflammation and necrosis of the pancreas result in the escape of amylase and lipase into the blood where increased levels can be measured. The origin of the normal blood level of amylase and lipase is uncertain and these concentrations probably have no physiologic function.U Both of these enzymes are cleared from blood primarily by the kidney. Determinations of serum amylase activity are done by one of two general methods-amyloclastic or saccharogenic. In the amyloclastic method, the disappearance of starch when incubated with serum is measured. This is the preferred procedure for the dog. Falsely increased amylase values may be obtained in the saccharogenic procedure because canine serum contains maltase. This method measures the appearance of reducing substances formed by the action of amylase on starch. Maltase can also form such reducing groups. Newer saccharogenic procedures utilizing starch-dye combinations not affected by maltase are now availableY Lipase determinations are somewhat more difficult to perform, but with the availability of kits and commercial laboratories, it is now practical to routinely obtain these values. The relative value of serum amylase and lipase in the diagnosis of acute pancreatitis has long been a subject of debate. Since both enzymes are excreted in the urine, it is to be expected that renal insufficiency will result in increases in both serum amylase and lipase. The results of one study indicated that uremic dogs had up to two and one-half times the normal serum amylase. 8 Thus it is possible to incorrectly diagnose acute pancreatitis in a dog with hyperamylasemia due to inadequate renal function. It was recently suggested that a urine specific gravity might help resolve the problem. If the specific gravity is greater than 1.020 in the azotemic dog with hyperamylasemia, diagnosis of prerenal azotemia due to dehydration associated with acute pancreatitis is suggested. If the urine specific gravity is low ( l.O 10 ± 0.002), renal disease with retention hyperamylasemia is more likely.U The same guidelines would probably apply to the interpretation of serum lipase in azotemic dogs. Other situations in which serum amylase values have been reported to be nonspecifically elevated in dogs are stress 11 and following cortisone administration; 5 however, in another study in which serum amylase was
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measured in dogs stressed by anesthesia, surgery, and various diseases, no significant increases were found. 8 In none of these reports was the amylase elevated by nonspecific causes to the levels usually found in dogs with acute pancreatitis. It has been reported that people with acute pancreatitis accompanied by hyperlipemia may have falsely low serum and urine amylase values with either the amyloclastic 6 or saccharogenic methods. 21 The data suggested the presence of a circulating inhibitor of serum and urine amylase distinct from the elevated serum lipids. The true amylase levels in such patients could be "unmasked" by diluting the serum or urine sample (from 2 to l6X) with the phosphate buffer used in the amylase assay. 21 It has been commonly reported that in patients with acute pancreatitis, the serum amylase becomes increased before lipase and returns to normal more rapidly.u· 16 The results of more recent studies of experimental acute pancreatitis in dogs2 •10 and clinical acute pancreatitis in people 15 revealed that the levels of these enzymes in the serum tended to parallel one another throughout the disease course. In addition, a few people-with acute pancreatitis initially had normal serum amylase and lipase values. 15 Until prospective studies of clinical acute pancreatitis in animals are conducted, this question will remain unanswered, and one should obtain both serum amylase and lipase values whenever possible. It has been reported that there is increased renal permeability to amylase during acute pancreatitis in people. 22 This resulted in an increased ratio of urine amylase: creatinine, and it was suggested that this ratio could be used in the differential diagnosis of hyperamylasemia. 22 Others have found that the urine amylase:creatinine ratio is also increased in people with diabetic ketoacidosis and burns. 14 Similar studies in dogs and cats have not been reported. Due to the variation between methods and laboratories, it is advisable to establish normal amylase and lipase values in one particul~r laboratory. High amylase and lipase levels may also be found in ascitic fluid obtained by paracentesis in an animal with acute pancreatitis. Perforated, obstructed, or infarcted intestine can give rise to similar findings but usually to a lesser degree.
Hematology The results of hematologic examinations will vary depending upon the stage and severity of the inflammatory process as well as the amount of tissue involved. In the milder forms of interstitial edematous pancreatitis, few changes in the hemogram and leukogram are to be expected. Mild dehydration may cause a slight increase in the packed cell volume and plasma total solids. A mild neutrophilic leukocytosis with slight regenerative left shift may be present. In more severe cases which progress to hemmorhagic, necrotic inflammation, a more marked neu-
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trophilic leukocytosis characterized by a regenerative left shift is usually present. In especially severe cases, the demand for neutrophils may exceed the rate at which they can be supplied by the bone marrow, and a degenerative left shift results. Losses of fluid due to anorexia, vomiting, diarrhea, and sequestration around the inflamed pancreas may cause marked dehydration, which will usually be reflected by a comparable increase in the packed cell volume and plasma total solids. If dehydration is sufficiently severe to cause impaired renal perfusion, modestly increased BUN and creatinine values may be present. Fasting hyperlipemia may be present in animals with diabetes mellitus, hyperadrenocorticism, hypothyroidism, primary defects in lipid metabolism, and acute pancreatitis. 18 •19 In one report it was found that there was an electrophoretic pattern characterized by increased density of the beta lipoprotein band and altered migration of the alpha1 lipoproteins in dogs with acute pancreatitisY No figures are available to estimate the frequency of this phenomenon in dogs and cats. In a study of 48 people with acute pancreatitis, it has been reported that 39 per cent had fasting hypertriglyceridemia, of whom over half had hyperlipemic serum. 3 The exact mechanism of the hyperlipemia is not clearly understood. In one study of human acute pancreatitis, it was found that fasting hypertriglyceridemia persisted long after the inflammatory process had subsided. 4 In addition, the response to lipid ingestion was abnormal in that plasma lipid levels increased far more than similar responses in controls. It was concluded that the lipid abnormalities were not secondary to the acute pancreatitis but were present beforehand, and possibly played an intermediary role in the pathogenesis of the pancreatitis. 4 It has been postulated that since pancreatic lipase is presumably present in high levels in pancreatic capillaries and interstitial fluid, hypertriglyceridemia presents a large quantity of substrate to the enzyme. Hydrolysis could result in high local concentrations of free fatty acids which could cause inflammation and microthrombi in pancreatic capillaries and initiate acute pancreatitis. 12 Institution of a low fat diet (10 to 15 gm of fat per day) has been shown to markedly decrease serum triglycerides as well as reduce the frequency of acute pancreatitis in human patients with fasting hyperlipoproteinemia and recurrent pancreatitis. 7 Studies of serum lipids in dogs and cats apparently at risk of developing acute pancreatitis (obese, sedentary, middle-aged or older) might help identify those animals most susceptible. Such studies might also serve as guides to the effectiveness of dietary management with low fat diets.
Serum Calcium Decreases in serum calcium concentrations may be present in animals with acute pancreatitis. In people, similar findings have been thought to be due to extraskeletal calcium sequestration and/or an un-
ACUTE PANCREATITIS AND PANCREATIC ADENOCARCINOMA
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identified defect in bone metabolism. 23 Pancreatic lipase liberated from the inflamed pancreas could degrade neutral fats to fatty acids which in turn could bind calcium as soap. Firm whitish-tan nodules of soap are frequently observed around the pancreas in animals dying of acute pancreatitis. Occasionally these nodules may be observed radiographically. Methemalbumin Reports ()f experimental acute pancreatitis in animals 13 and the clinical syndrome in man 9 have documented the reliability of methemalbumin analysis in differentiating mild edematous pancreatitis from the hemorrhagic form. The analysis may also be done on plasma or ascitic fluid. Apparently, methemalbumin is formed as released pancreatic enzymes act on hemoglobin at the site of pancreatic hemorrhage and convert it to hematin. Hematin then combines with blood proteins including albumin.U Although hematin may also be formed in other conditions (hemolytic dyscrasias and intestinal infarction), the detection of methemalbumin in patients with a history and enzyme studies compatible with acute pancreatitis should be considered highly suggestive of the hemorrhagic form of acute pancreatitis. A simplified procedure for methemalbumin analysis has been published. 20 Studies of methemalbumin in clinical cases of acute pancreatitis in dogs and cats are needed to establish the value of this procedure. Disseminated Intravascular Coagulation Coagulation abnormalities such as disseminated intravascular coagulation have been associated with acute pancreatitis.U It is likely that the clotting mechanism is activated diffusely by high levels of circulating pancreatic enzymes with resultant depletion of clotting factors. Laboratory tests commonly employed to diagnose disseminated intravascular coagulation and monitor subsequent heparin therapy include the activated clotting time, platelet count, fibrinogen level, prothrombin and partial thromboplastin times, and level of fibrin degradation products. Blood Gases and pH It is unlikely that animals with mild edematous pancreatitis will have significant alterations in blood P0 2 , PC02 , pH, or bicarbonate (HC03). In those more severely affected, losses of alkaline pancreatic and biliary secretions through vomiting and sequestration in the intestines, as well as dehydration and resultant impairment of renal perfusion, will probably cause metabolic acidosis. If shock is present, anaerobic metabolism with the production of lactic acid can increase the severity of the metabolic acidosis. In human acute pancreatitis, respiratory insufficiency characterized by low PaOz values were found in over half of 116' patients during the initial 48 hours of hospitalization. 17 Although the pathogenesis was unclear, it was suggested that high circulating levels of
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pancreatic enzymes could cause loss of pulmonary surfactant, intravascular coagulation, and pulmonary microemboli. It was concluded that frequent early hypoxia in acute pancreatitis necessitates close blood gas monitoringY Reports of blood gas studies in animals with acute pancreatitis are not available. Monitoring the Response to Therapy
Generally, the ability of the animal to retain progressively larger quantities of food (after 2 to 3 day fast) without further vomiting is used as the primary guide in assessing whether or not the pancreatic inflammation is subsiding. Periodic complete blood counts and serum amylase and lipase determinations may also be helpful in making this assessment. The adequacy of fluid volume replacement can be assessed by looking for improvement in skin elasticity and capillary refilling time in the gums. Monitoring blood pressure with an indirect ultrasound instrument* is quite useful in guiding appropriate fluid therapy and managing shock, especially when evaluated in conjunction with the central venous pressure. Periodically checking the packed cell volume, plasma total solids, and BUN will also help in assessing the results of fluid therapy. More precise therapy for electrolyte and blood gas/pH disturbances can be given if these determinations are made intermittently. In more critical patients, such laboratory guidance can mean the difference between a successful outcome and death of the patient. Complications of Acute Pancreatitis
Among the potential complications of acute pancreatitis are secondary bacterial infections (pancreatic abscessation, peritonitis), obstructive icterus due to encroachment of the inflammatory process on the common bile duct, diabetes mellitus, and pancreatic exocrine insufficiency. The use of the laboratory in evaluating these disorders is discussed in other sections. It is probably wise to measure the fasting blood glucose concentration one month or so after the signs of acute pancreatitis have subsided and periodically thereafter. Values in the range of 120 to 200 mgll 00 ml should alert the clinician to the possibility of early diabetes mellitus. A high-dose intravenous glucose tolerance test should be done to evaluate such animals. 10 (See the article on diabetes mellitus in this symposium.) Signs such as weight loss despite a good appetite, and greasy, bulky, malodorous feces may herald the onset of pancreatic exocrine insufficiency. If such signs are observed, the feces should be examined for trypsin and the presence of excessive fat, starch, and undigested protein (see pancreatic exocrine insufficiency).
*Arteriosonde 1010. Roche Medical Electronics, Cr;mbury, New Jersey.
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PANCREATIC ADENOCARCINOMA Adenocarcinomas of the pancreas are uncommon in dogs and especially in cats. When diagnosed, they are usually found in older animals. In one survey, the mean age of affected animals was 10.8 years (range 5.5 to 16.0 years). 1 Extensive metastasis to regional nodes and other organs, notably the liver, tends to occur early. Therefore, clinical signs and laboratory results commonly relate to the organs secondarily infiltrated by metastatic masses and not to the pancreas itself. Hepatic involvement may result in icterus (hyperbilirubinemia) due to biliary obstruction and hepatocellular damage. Increases in both serum alkaline phosphatase (SAP) and SGPT are commonly found with the SAP being increased out of proportion to the SGPT due to biliary stasis (see hepatic disorders). Occasionally, the signs of pancreatic adenocarcinoma will closely resemble those of acute pancreatitis. In such instances, serum amylase and lipase values are usually increased. If ascitic fluid is present, paracentesis should be done and the fluid analyzed for amylase and lipase as well as examined microscopically. Neoplastic cells may sometimes be identified in new methylene blue stained smears, although it is generally not possible to identify their source. Ultimately, an exploratory celiotomy may be needed to establish the diagnosis.
REFERENCES AcuTE PANCREATITIS
l. Brobst, D. F.: Pancreatic function. In Kaneko J. J. (ed.): Clinical Biochemistry of Domestic Animals. Edition 2, Vol. I. New York, Academic Press, 1970. 2. Brobst, D., Ferguson, A. B., and Carter,]. M.: Evaluation of serum amylase and lipase activity in experimentally-induced pancreatitis in the dog. J.A.V.M.A., 157:1697, 1970. 3. Cameron, J. L., Capuzzi, D. M., Zuidema, G. D., eta!.: Acute pancreatitis with hyperlipemia: The incidence of lipid abnormalities in acute pancreatitis. Ann. Surg., 177:483, 1973. 4. Cameron,]. L., Capuzzi, D. M., Zuidema, G. D., eta!.: Acute pancreatitis with hyperlipemia. Am. J. Med., 56:482, 1974. 5. Challis, T. W., Reid, L. C., and Hinton, J. W.: Study of some factors which influence the level of serum amylase in dogs and humans. Gastroenterology, 33:818, 1957. 6. Fallat, R. W., Vester, J. W., and Glueck, C. J.: Suppression of amylase activity by hypertriglyceridemia. ].A.M.A., 225: 1331, 1973. 7. Farmer, R. G., Winkelman, E. 1., and Brown, H. B.: Hyperlipoproteinemia and pancreatitis. Am.J. Med.,54:161, 1973. 8. Finco, D. R., and Stevens, J. B.: Clinical significance of serum amylase activity in the dog.J.A.V.M.A., 155:1686, 1969. 9. Geokas, M. C., Rinderknecht, H., Walberg, C. B., et al.: Methemalbumin in the diagnosis of acute hemorrhagic pancreatitis. Ann. Intern. Med., 81:483, 1974.
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10. Greve, T., Dayton, A. D., and Anderson, N. V.: Acute pancreatitis with co-existent diabetes mellitus: An experimental study in the dog. Am.]. Vet. Res., 34:939, I 973. II. Hardy, R. M., and Stevens,]. B.: Exocrine pancreatic diseases. In Ettinger, S.]. (ed.): Textbook of Veterinary Internal Medicine. Philadelphia, W. B. Sauders Co., I975. 12. Havel, R. ].: Pathogenesis, differentiation, and management of hypertriglyceridemia. Adv. Int. Med., 15:II7, I969. 13. Kelly, T. R., Klein, R. L., and Porquez,]. M.: Methemalbumin in acute pancreatitis: An experimental and clinical appraisal. Ann. Surg., 175:I5, 1972. 14. Levine, R.I., Glauser, F. L., and Berk,]. E.: Enhancement of the amylase-creatinine clearance ratio in disorders other than acute pancreatitis. New Engl. ]. Med., 292:329, 1975. 15. Lifton, L. J., Slickers, K. A., Pragay, D. A., eta!.: Pancreatitis and lipase. ].A.M.A., 229:47, 1974. 16. Perman, V., Stevens, ]. B.: Clinical evaluation of the acinar pancreas of the dog. J.A.V.M.A., 155:2053, I969. I7. Ranson, J.H.C., Turner,]. W., Roses, D. F., eta!.: Respiratory complications in acute pancreatitis. Ann. Surg., 179:557, I974. 18. Rogers, W. A., Donovan, E. F., and Kociba, G.].: Idiopathic hyperlipoproteinemia in dogs. J.A.V.M.A., 166:1087, 1975. 19. Rogers, W. A., Donovan, E. F., and Kociba, G.].: Lipids and lipoproteins in normal dogs and in dogs with secondary hyperlipoproteinemia. J.A.V.M.A., 166:1092, 1975. 20. Walberg, C. B., Geokas, M. C., and Rinderknecht, H.: Determination of serum methemalbumin. Clin. Chim. Acta, 48:229, 1973. 21. Warshaw, A. L., Bellini, C. A., and Lesser, P. B.: Inhibition of serum and urine amylase activity in pancreatitis with hyperlipemia. Ann. Surg., 182:72, 1975. 22. Warshaw, A. L., and Fuller, A. F.: Specificity of increased renal clearance of amylase in diagnosis of acute pancreatitis. New Engl.]. Med., 292:325, 1975. 23. Weir, G. C., Lesser, P. B., Drop, L. J., eta!.: The hypocalcemia of acute pancreatitis. Ann. Intern. Med., 83: I85, I 975.
PANCREATIC ADENOCARCINOMA
I. Anderson, N. V., and Johnson, K. H.: Pancreatic carcinoma in the dog. J.A.V.M.A., 150:286, I967. Department of Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia 30602
Laboratory Diagnosis of Acute Pancreatitis and Pancreatic Adenocarcinoma Larry M. Cornelius, D.V.M., Ph.D.*
ACUTE PANCREATITIS Inflammatory disorders of the pancreas may be either acute or chronic. In general, the etiology is poorly understood, and indeed, it is likely that a variety of causes may initiate a series of pathophysiologic events which culminate in acute or chronic pancreatitis. Just as the etiologies and pathophysiology have not been well defined, the clinical signs also may be misinterpreted due to their similarity to signs caused by other more common disorders. The purpose of this discussion is to familiarize the practicing veterinarian with the various laboratory procedures thought to be most useful in the diagnosis and management of acute pancreatitis. Emphasis will be given to their proper interpretation. Laboratory Findings As has been previously reported, acute pancreatitis is a disease of extreme variability.U This is probably because the inflammatory process may be limited to a fairly mild interstitial edema or may be a fulminant hemorrhagic, necrotic inflammation. Ability to diagnose acute pancreatitis by laboratory means may depend upon the type and severity of inflammation present and the duration of the process. Acute pancreatitis should be most highly suspected in the obese, sedentary, middle-aged to older house pet which consumes a high fat diet. Episodes of anorexia, vomiting, and abdominal pain in this type animal should always alert the clinician to the possibility of acute pancreatitis. Although the disorder is usually self-limiting, diagnostic procedures should not be delayed since the disease can sometimes progress rapidly into shock and death. *Associate Professor, Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, Georgia Veterinary Clinics of North America-Vol. 6, No.4, November 1976
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It should be emphasized that no single laboratory test is specific enough to be diagnostic of acute pancreatitis. In dealing with any complicated internal medical disorder, the clinician must always evaluate ancillary tests in light of his clinical observations. This is certainly true when considering a diagnosis of acute pancreatitis.
Serum Amylase and Lipase Serum amylase and lipase are still the most heavily relied upon tests to help confirm or refute the presence of acute pancreatic inflammation. These enzymes are produced in the pancreatic acinar cells and are normally secreted into the pancreatic ductular system for transport to the duodenum. Inflammation and necrosis of the pancreas result in the escape of amylase and lipase into the blood where increased levels can be measured. The origin of the normal blood level of amylase and lipase is uncertain and these concentrations probably have no physiologic function.U Both of these enzymes are cleared from blood primarily by the kidney. Determinations of serum amylase activity are done by one of two general methods-amyloclastic or saccharogenic. In the amyloclastic method, the disappearance of starch when incubated with serum is measured. This is the preferred procedure for the dog. Falsely increased amylase values may be obtained in the saccharogenic procedure because canine serum contains maltase. This method measures the appearance of reducing substances formed by the action of amylase on starch. Maltase can also form such reducing groups. Newer saccharogenic procedures utilizing starch-dye combinations not affected by maltase are now availableY Lipase determinations are somewhat more difficult to perform, but with the availability of kits and commercial laboratories, it is now practical to routinely obtain these values. The relative value of serum amylase and lipase in the diagnosis of acute pancreatitis has long been a subject of debate. Since both enzymes are excreted in the urine, it is to be expected that renal insufficiency will result in increases in both serum amylase and lipase. The results of one study indicated that uremic dogs had up to two and one-half times the normal serum amylase. 8 Thus it is possible to incorrectly diagnose acute pancreatitis in a dog with hyperamylasemia due to inadequate renal function. It was recently suggested that a urine specific gravity might help resolve the problem. If the specific gravity is greater than 1.020 in the azotemic dog with hyperamylasemia, diagnosis of prerenal azotemia due to dehydration associated with acute pancreatitis is suggested. If the urine specific gravity is low ( l.O 10 ± 0.002), renal disease with retention hyperamylasemia is more likely.U The same guidelines would probably apply to the interpretation of serum lipase in azotemic dogs. Other situations in which serum amylase values have been reported to be nonspecifically elevated in dogs are stress 11 and following cortisone administration; 5 however, in another study in which serum amylase was
ACUTE PANCREATITIS AND PANCREATIC ADENOCARCINOMA
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measured in dogs stressed by anesthesia, surgery, and various diseases, no significant increases were found. 8 In none of these reports was the amylase elevated by nonspecific causes to the levels usually found in dogs with acute pancreatitis. It has been reported that people with acute pancreatitis accompanied by hyperlipemia may have falsely low serum and urine amylase values with either the amyloclastic 6 or saccharogenic methods. 21 The data suggested the presence of a circulating inhibitor of serum and urine amylase distinct from the elevated serum lipids. The true amylase levels in such patients could be "unmasked" by diluting the serum or urine sample (from 2 to l6X) with the phosphate buffer used in the amylase assay. 21 It has been commonly reported that in patients with acute pancreatitis, the serum amylase becomes increased before lipase and returns to normal more rapidly.u· 16 The results of more recent studies of experimental acute pancreatitis in dogs2 •10 and clinical acute pancreatitis in people 15 revealed that the levels of these enzymes in the serum tended to parallel one another throughout the disease course. In addition, a few people-with acute pancreatitis initially had normal serum amylase and lipase values. 15 Until prospective studies of clinical acute pancreatitis in animals are conducted, this question will remain unanswered, and one should obtain both serum amylase and lipase values whenever possible. It has been reported that there is increased renal permeability to amylase during acute pancreatitis in people. 22 This resulted in an increased ratio of urine amylase: creatinine, and it was suggested that this ratio could be used in the differential diagnosis of hyperamylasemia. 22 Others have found that the urine amylase:creatinine ratio is also increased in people with diabetic ketoacidosis and burns. 14 Similar studies in dogs and cats have not been reported. Due to the variation between methods and laboratories, it is advisable to establish normal amylase and lipase values in one particul~r laboratory. High amylase and lipase levels may also be found in ascitic fluid obtained by paracentesis in an animal with acute pancreatitis. Perforated, obstructed, or infarcted intestine can give rise to similar findings but usually to a lesser degree.
Hematology The results of hematologic examinations will vary depending upon the stage and severity of the inflammatory process as well as the amount of tissue involved. In the milder forms of interstitial edematous pancreatitis, few changes in the hemogram and leukogram are to be expected. Mild dehydration may cause a slight increase in the packed cell volume and plasma total solids. A mild neutrophilic leukocytosis with slight regenerative left shift may be present. In more severe cases which progress to hemmorhagic, necrotic inflammation, a more marked neu-
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trophilic leukocytosis characterized by a regenerative left shift is usually present. In especially severe cases, the demand for neutrophils may exceed the rate at which they can be supplied by the bone marrow, and a degenerative left shift results. Losses of fluid due to anorexia, vomiting, diarrhea, and sequestration around the inflamed pancreas may cause marked dehydration, which will usually be reflected by a comparable increase in the packed cell volume and plasma total solids. If dehydration is sufficiently severe to cause impaired renal perfusion, modestly increased BUN and creatinine values may be present. Fasting hyperlipemia may be present in animals with diabetes mellitus, hyperadrenocorticism, hypothyroidism, primary defects in lipid metabolism, and acute pancreatitis. 18 •19 In one report it was found that there was an electrophoretic pattern characterized by increased density of the beta lipoprotein band and altered migration of the alpha1 lipoproteins in dogs with acute pancreatitisY No figures are available to estimate the frequency of this phenomenon in dogs and cats. In a study of 48 people with acute pancreatitis, it has been reported that 39 per cent had fasting hypertriglyceridemia, of whom over half had hyperlipemic serum. 3 The exact mechanism of the hyperlipemia is not clearly understood. In one study of human acute pancreatitis, it was found that fasting hypertriglyceridemia persisted long after the inflammatory process had subsided. 4 In addition, the response to lipid ingestion was abnormal in that plasma lipid levels increased far more than similar responses in controls. It was concluded that the lipid abnormalities were not secondary to the acute pancreatitis but were present beforehand, and possibly played an intermediary role in the pathogenesis of the pancreatitis. 4 It has been postulated that since pancreatic lipase is presumably present in high levels in pancreatic capillaries and interstitial fluid, hypertriglyceridemia presents a large quantity of substrate to the enzyme. Hydrolysis could result in high local concentrations of free fatty acids which could cause inflammation and microthrombi in pancreatic capillaries and initiate acute pancreatitis. 12 Institution of a low fat diet (10 to 15 gm of fat per day) has been shown to markedly decrease serum triglycerides as well as reduce the frequency of acute pancreatitis in human patients with fasting hyperlipoproteinemia and recurrent pancreatitis. 7 Studies of serum lipids in dogs and cats apparently at risk of developing acute pancreatitis (obese, sedentary, middle-aged or older) might help identify those animals most susceptible. Such studies might also serve as guides to the effectiveness of dietary management with low fat diets.
Serum Calcium Decreases in serum calcium concentrations may be present in animals with acute pancreatitis. In people, similar findings have been thought to be due to extraskeletal calcium sequestration and/or an un-
ACUTE PANCREATITIS AND PANCREATIC ADENOCARCINOMA
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identified defect in bone metabolism. 23 Pancreatic lipase liberated from the inflamed pancreas could degrade neutral fats to fatty acids which in turn could bind calcium as soap. Firm whitish-tan nodules of soap are frequently observed around the pancreas in animals dying of acute pancreatitis. Occasionally these nodules may be observed radiographically. Methemalbumin Reports ()f experimental acute pancreatitis in animals 13 and the clinical syndrome in man 9 have documented the reliability of methemalbumin analysis in differentiating mild edematous pancreatitis from the hemorrhagic form. The analysis may also be done on plasma or ascitic fluid. Apparently, methemalbumin is formed as released pancreatic enzymes act on hemoglobin at the site of pancreatic hemorrhage and convert it to hematin. Hematin then combines with blood proteins including albumin.U Although hematin may also be formed in other conditions (hemolytic dyscrasias and intestinal infarction), the detection of methemalbumin in patients with a history and enzyme studies compatible with acute pancreatitis should be considered highly suggestive of the hemorrhagic form of acute pancreatitis. A simplified procedure for methemalbumin analysis has been published. 20 Studies of methemalbumin in clinical cases of acute pancreatitis in dogs and cats are needed to establish the value of this procedure. Disseminated Intravascular Coagulation Coagulation abnormalities such as disseminated intravascular coagulation have been associated with acute pancreatitis.U It is likely that the clotting mechanism is activated diffusely by high levels of circulating pancreatic enzymes with resultant depletion of clotting factors. Laboratory tests commonly employed to diagnose disseminated intravascular coagulation and monitor subsequent heparin therapy include the activated clotting time, platelet count, fibrinogen level, prothrombin and partial thromboplastin times, and level of fibrin degradation products. Blood Gases and pH It is unlikely that animals with mild edematous pancreatitis will have significant alterations in blood P0 2 , PC02 , pH, or bicarbonate (HC03). In those more severely affected, losses of alkaline pancreatic and biliary secretions through vomiting and sequestration in the intestines, as well as dehydration and resultant impairment of renal perfusion, will probably cause metabolic acidosis. If shock is present, anaerobic metabolism with the production of lactic acid can increase the severity of the metabolic acidosis. In human acute pancreatitis, respiratory insufficiency characterized by low PaOz values were found in over half of 116' patients during the initial 48 hours of hospitalization. 17 Although the pathogenesis was unclear, it was suggested that high circulating levels of
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pancreatic enzymes could cause loss of pulmonary surfactant, intravascular coagulation, and pulmonary microemboli. It was concluded that frequent early hypoxia in acute pancreatitis necessitates close blood gas monitoringY Reports of blood gas studies in animals with acute pancreatitis are not available. Monitoring the Response to Therapy
Generally, the ability of the animal to retain progressively larger quantities of food (after 2 to 3 day fast) without further vomiting is used as the primary guide in assessing whether or not the pancreatic inflammation is subsiding. Periodic complete blood counts and serum amylase and lipase determinations may also be helpful in making this assessment. The adequacy of fluid volume replacement can be assessed by looking for improvement in skin elasticity and capillary refilling time in the gums. Monitoring blood pressure with an indirect ultrasound instrument* is quite useful in guiding appropriate fluid therapy and managing shock, especially when evaluated in conjunction with the central venous pressure. Periodically checking the packed cell volume, plasma total solids, and BUN will also help in assessing the results of fluid therapy. More precise therapy for electrolyte and blood gas/pH disturbances can be given if these determinations are made intermittently. In more critical patients, such laboratory guidance can mean the difference between a successful outcome and death of the patient. Complications of Acute Pancreatitis
Among the potential complications of acute pancreatitis are secondary bacterial infections (pancreatic abscessation, peritonitis), obstructive icterus due to encroachment of the inflammatory process on the common bile duct, diabetes mellitus, and pancreatic exocrine insufficiency. The use of the laboratory in evaluating these disorders is discussed in other sections. It is probably wise to measure the fasting blood glucose concentration one month or so after the signs of acute pancreatitis have subsided and periodically thereafter. Values in the range of 120 to 200 mgll 00 ml should alert the clinician to the possibility of early diabetes mellitus. A high-dose intravenous glucose tolerance test should be done to evaluate such animals. 10 (See the article on diabetes mellitus in this symposium.) Signs such as weight loss despite a good appetite, and greasy, bulky, malodorous feces may herald the onset of pancreatic exocrine insufficiency. If such signs are observed, the feces should be examined for trypsin and the presence of excessive fat, starch, and undigested protein (see pancreatic exocrine insufficiency).
*Arteriosonde 1010. Roche Medical Electronics, Cr;mbury, New Jersey.
ACUTE PANCREATITIS AND PANCREATIC ADENOCARCINOMA
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PANCREATIC ADENOCARCINOMA Adenocarcinomas of the pancreas are uncommon in dogs and especially in cats. When diagnosed, they are usually found in older animals. In one survey, the mean age of affected animals was 10.8 years (range 5.5 to 16.0 years). 1 Extensive metastasis to regional nodes and other organs, notably the liver, tends to occur early. Therefore, clinical signs and laboratory results commonly relate to the organs secondarily infiltrated by metastatic masses and not to the pancreas itself. Hepatic involvement may result in icterus (hyperbilirubinemia) due to biliary obstruction and hepatocellular damage. Increases in both serum alkaline phosphatase (SAP) and SGPT are commonly found with the SAP being increased out of proportion to the SGPT due to biliary stasis (see hepatic disorders). Occasionally, the signs of pancreatic adenocarcinoma will closely resemble those of acute pancreatitis. In such instances, serum amylase and lipase values are usually increased. If ascitic fluid is present, paracentesis should be done and the fluid analyzed for amylase and lipase as well as examined microscopically. Neoplastic cells may sometimes be identified in new methylene blue stained smears, although it is generally not possible to identify their source. Ultimately, an exploratory celiotomy may be needed to establish the diagnosis.
REFERENCES AcuTE PANCREATITIS
l. Brobst, D. F.: Pancreatic function. In Kaneko J. J. (ed.): Clinical Biochemistry of Domestic Animals. Edition 2, Vol. I. New York, Academic Press, 1970. 2. Brobst, D., Ferguson, A. B., and Carter,]. M.: Evaluation of serum amylase and lipase activity in experimentally-induced pancreatitis in the dog. J.A.V.M.A., 157:1697, 1970. 3. Cameron, J. L., Capuzzi, D. M., Zuidema, G. D., eta!.: Acute pancreatitis with hyperlipemia: The incidence of lipid abnormalities in acute pancreatitis. Ann. Surg., 177:483, 1973. 4. Cameron,]. L., Capuzzi, D. M., Zuidema, G. D., eta!.: Acute pancreatitis with hyperlipemia. Am. J. Med., 56:482, 1974. 5. Challis, T. W., Reid, L. C., and Hinton, J. W.: Study of some factors which influence the level of serum amylase in dogs and humans. Gastroenterology, 33:818, 1957. 6. Fallat, R. W., Vester, J. W., and Glueck, C. J.: Suppression of amylase activity by hypertriglyceridemia. ].A.M.A., 225: 1331, 1973. 7. Farmer, R. G., Winkelman, E. 1., and Brown, H. B.: Hyperlipoproteinemia and pancreatitis. Am.J. Med.,54:161, 1973. 8. Finco, D. R., and Stevens, J. B.: Clinical significance of serum amylase activity in the dog.J.A.V.M.A., 155:1686, 1969. 9. Geokas, M. C., Rinderknecht, H., Walberg, C. B., et al.: Methemalbumin in the diagnosis of acute hemorrhagic pancreatitis. Ann. Intern. Med., 81:483, 1974.
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10. Greve, T., Dayton, A. D., and Anderson, N. V.: Acute pancreatitis with co-existent diabetes mellitus: An experimental study in the dog. Am.]. Vet. Res., 34:939, I 973. II. Hardy, R. M., and Stevens,]. B.: Exocrine pancreatic diseases. In Ettinger, S.]. (ed.): Textbook of Veterinary Internal Medicine. Philadelphia, W. B. Sauders Co., I975. 12. Havel, R. ].: Pathogenesis, differentiation, and management of hypertriglyceridemia. Adv. Int. Med., 15:II7, I969. 13. Kelly, T. R., Klein, R. L., and Porquez,]. M.: Methemalbumin in acute pancreatitis: An experimental and clinical appraisal. Ann. Surg., 175:I5, 1972. 14. Levine, R.I., Glauser, F. L., and Berk,]. E.: Enhancement of the amylase-creatinine clearance ratio in disorders other than acute pancreatitis. New Engl. ]. Med., 292:329, 1975. 15. Lifton, L. J., Slickers, K. A., Pragay, D. A., eta!.: Pancreatitis and lipase. ].A.M.A., 229:47, 1974. 16. Perman, V., Stevens, ]. B.: Clinical evaluation of the acinar pancreas of the dog. J.A.V.M.A., 155:2053, I969. I7. Ranson, J.H.C., Turner,]. W., Roses, D. F., eta!.: Respiratory complications in acute pancreatitis. Ann. Surg., 179:557, I974. 18. Rogers, W. A., Donovan, E. F., and Kociba, G.].: Idiopathic hyperlipoproteinemia in dogs. J.A.V.M.A., 166:1087, 1975. 19. Rogers, W. A., Donovan, E. F., and Kociba, G.].: Lipids and lipoproteins in normal dogs and in dogs with secondary hyperlipoproteinemia. J.A.V.M.A., 166:1092, 1975. 20. Walberg, C. B., Geokas, M. C., and Rinderknecht, H.: Determination of serum methemalbumin. Clin. Chim. Acta, 48:229, 1973. 21. Warshaw, A. L., Bellini, C. A., and Lesser, P. B.: Inhibition of serum and urine amylase activity in pancreatitis with hyperlipemia. Ann. Surg., 182:72, 1975. 22. Warshaw, A. L., and Fuller, A. F.: Specificity of increased renal clearance of amylase in diagnosis of acute pancreatitis. New Engl.]. Med., 292:325, 1975. 23. Weir, G. C., Lesser, P. B., Drop, L. J., eta!.: The hypocalcemia of acute pancreatitis. Ann. Intern. Med., 83: I85, I 975.
PANCREATIC ADENOCARCINOMA
I. Anderson, N. V., and Johnson, K. H.: Pancreatic carcinoma in the dog. J.A.V.M.A., 150:286, I967. Department of Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia 30602