Suspected isolated pancreatic lipase deficiency in a dog xenoulis et al 2007 journal of veterinary i

J Vet Intern Med 2007;21:1113–1116

Suspected Isolated Pancreatic Lipase Deficiency in a Dog Panagiotis G. Xenoulis, Jonathan M. Fradkin, Steven W. Rapp, Jan S. Suchodolski, and Jo¨rg M. Steiner 4-month-old female Siberian Husky was referred for a 2-month history of intermittent diarrhea, poor body condition, polyuria, and polydipsia. Based on the history, the diarrhea was thought to be of small intestinal or mixed origin because the dog had a ravenous appetite, poor body condition and failure to thrive, frequent defecations, and feces that occasionally were covered by mucus. The dog had been diagnosed with and repeatedly treated for hookworms and coccidia by the referring veterinarian with a combination of praziquantel, pyrantel pamoate, and febantel,a and metronidazole.b The dog also had been treated with amoxicillin,c sulfadimethoxine,d and prednisonee for short periods of time. Two weeks before presentation, the referring veterinarian changed the dog’s regular dietf to a prescription dietg formulated for dogs with gastrointestinal disease. The antiparasitic medications, antibiotics, glucocorticoids, and diet change led only to transient responses, and the diarrhea always recurred with discontinuation of therapy despite the fact that both direct fecal examination and fecal flotation were negative. The dog’s appetite was increased for the entire period of 2 months.

At the time of presentation, the dog weighed 12 kg and was in poor body condition (body condition score 3/ 9; optimal, 5/9).1 Slightly thickened, gas-filled intestinal loops were identified by abdominal palpation. CBC and serum electrolyte concentrations were within normal limits. A serum biochemical profile revealed mild increases in alkaline phosphatase activity (ALP, 187 U/L; reference range, 10–150 U/L), creatine kinase activity (CK, 421 U/L; reference range, 10–200 U/L), and serum phosphorus concentration (8.8 mg/dL; reference range, 2.1–6.3 mg/dL), and a mild decrease in blood urea nitrogen concentration (BUN, 4 mg/dL; reference range, 7–27 mg/dL). Liver disease was suspected, and fasting and 2-hour postprandial total serum bile acid concentrations were evaluated and found to be normal (fasting serum bile acid concentration, ,1.0 mM/L;

A

From the Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences (Xenoulis, Suchodolski, Steiner); and the Department of Small Animal Clinical Sciences (Fradkin), College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX; the San Antonio Veterinary Referral Specialists, San Antonio, TX (Fradkin); and the Boerne Veterinary Clinic, Boerne, TX (Rapp).

Reprint requests: Dr Panagiotis G. Xenoulis, Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4474 TAMU, TX 77843; e-mail: pxenoulis@cvm.tamu. edu.

Submitted December 20, 2006; Revised March 18, 2007; Accepted April 20, 2007.

Copyright E 2007 by the American College of Veterinary Internal Medicine 0891-6640/07/2105-0024/$3.00/0

reference range, 0–5 mM/L; postprandial serum bile acid concentration, 1.5 mM/L; reference range, 3.9– 12.7 mM/L). A relatively low specific gravity (1.017) was noted on urinalysis, and bacterial culture of urine yielded no growth.

Radiographs of the abdomen were normal, but the layers of the small intestinal wall could not be differentiated on abdominal ultrasonography, and a prominent pancreas of normal echogenicity was identified. Serum concentrations of cobalamin, folate, canine pancreatic lipase immunoreactivity (measured as Spec cPLh), and canine trypsin-like immunoreactivity (cTLI) were determined and results of these tests were Spec cPL ,29 mg/L (below the detection limit; reference range, 29–200 mg/L), cTLI 7.1 mg/L (reference range, 5.0–35.0 mg/L), cobalamin 1,001 ng/L (reference range, 249–733 ng/L), folate 39.3 mg/L (reference range, 6.5– 11.5 mg/L). These findings were interpreted as consistent with small intestinal bacterial overgrowth (SIBO), also referred to as antibiotic-responsive diarrhea. Because of the history of chronic diarrhea and poor body condition in conjunction with a ravenous appetite, exocrine pancreatic insufficiency (EPI) was suspected, and reevaluation of serum cTLI concentration 2 weeks later was recommended. The owner was instructed to feed a low fat diet.i Two weeks later (day 14), another blood sample was obtained from the dog for measurement of serum cTLI concentration, and the result again was within normal limits (7.4 mg/L). The owner stated that there had been marked improvement of diarrhea while the dog was on the canned low fat diet.i Body condition score had improved slightly (3.5/9), and body weight had increased by 1 kg (weight, 13 kg). Physical examination was otherwise unchanged.

After 2 more weeks (day 28), the dog returned to the referring veterinarian for reevaluation. During the preceding 2 weeks, the dog had exhibited only a few bouts of diarrhea, which the owner associated with the administration of the dry form of the low fat diet.

Polyuria and polydipsia had resolved. At this time, isolated pancreatic lipase deficiency was suspected due to the 2 normal cTLI results, and serum canine pancreatic lipase immunoreactivity (cPLI) concentration was measured on a second serum sample. In addition, a therapeutic trial with pancreatic enzymej supplementation was initiated (1 teaspoon mixed with food q12h).

Approximately 4 weeks later (day 56), the dog was returned to the referring veterinarian for ovariohysterectomy. During the procedure, biopsies were obtained from the small and large intestines and from the pancreas. During the previous 4 weeks, diarrhea had resolved except for 1 episode associated with dietary indiscretion, and the dog had also gained weight.

Histologic evaluation of pancreatic and intestinal biopsy specimens indicated normal pancreas and colon.

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The small intestinal biopsy specimens revealed mild to moderate focal infiltration of the mucosa with lymphocytes, plasma cells, and eosinophils. No other histopathologic abnormalities (eg, villus atrophy, mucosal architectural disruption) were found. Results of serum pancreatic lipase immunoreactivity (measured by a different assay than the one initially used) indicated undetectable serum cPLI concentration (lower detection limit, 0.4 mg/L; reference range, 2.2–102.1 mg/L).2 The therapeutic protocol remained the same (low fat dieti and pancreatic enzymej supplementation). Over the next 3 weeks, the owner reported that the dog was doing well and had only a few episodes of diarrhea. During this period, the owners moved and referral care responsibility was transferred. The dog was reevaluated approximately 5 weeks later (day 91) by another veterinary internist.

The dog had been on a venison and potato dietk for the previous 4 weeks. This diet was initiated for treatment of possible inflammatory bowel disease during the time the biopsies were being evaluated and was continued at the owner’s request after test results were received. The dog remained on pancreatic enzyme supplementation. The dog did not have any episodes of diarrhea during these 5 weeks and had gained approximately 5 kg (weight, 20 kg; body condition score, 4.5/9) over the last month.

Isolated pancreatic lipase deficiency, a mono-enzymatic form of EPI, has been described rarely in human beings but has never been reported in dogs or cats.3–9,l In humans, this disorder is congenital and of unknown cause. The most common clinical sign is steatorrhea, which usually starts early in life, and failure to thrive is noted only occasionally. Systemic manifestations usually are absent. In human patients, the diagnosis usually is made by identification of low or absent lipase activity in the duodenum after stimulation of the pancreas with pancreozymin-secretin.3–8,l Immunologic detection of pancreatic lipase (which exclusively measures lipase of pancreatic origin) also has been used for the diagnosis of this disease.4,7 This disorder is treated by pancreatic enzyme supplementation.

In the present case, the age of onset of clinical signs (8 weeks) strongly suggests a congenital defect. The dog responded well to a low fat diet, and the diarrhea completely resolved after pancreatic enzyme supplementation. This scenario strongly suggests a congenital pancreatic defect that causes EPI, but results of 2 different measurements of serum cTLI concentrations were within the reference range and suggested that classical EPI was very unlikely in this dog.10 At the same time, serum cPLI concentration, which specifically measures the amount of pancreatic lipase concentration in serum, was below the lower detection limit of the assay, suggesting an isolated deficiency of this enzyme.2 Pancreatic lipase is produced by pancreatic acinar cells and secreted into the pancreatic duct. Small amounts of pancreatic lipase, however, leak into the circulation leading to detectable amounts of pancreatic lipase in the serum of healthy dogs, which can be measured by pancreatic lipase-specific immunoassays.

Serum cPLI concentrations have been shown to be highly specific for pancreatic lipase. In an immunolocalization study, staining for canine pancreatic lipase was found to be limited to the exocrine pancreas, and other proteins that may cross-immunoreact with canine pancreatic lipase were not detected in any of the 37 nonpancreatic tissues evaluated.11 In another study, there was nearly total absence of detectable cPLI in the serum of dogs with EPI.9 Canine pancreatic lipase concentration was measured by 2 different immunoassays: serum Spec cPL and serum cPLI. Serum Spec cPL concentration, which was determined upon initial presentation, was ,29 mg/L, which is below the detection limit of the assay. At reevaluation, canine pancreatic lipase was measured by the original cPLI assay, which has a lower detection limit compared with the Spec cPL assay. cPLI concentrations also were below the limit of detection of the cPLI assay. The early onset of clinical signs (chronic diarrhea and poor body condition), the absence of hematologic and biochemical abnormalities, the normal cTLI and undetectable cPLI concentrations, and finally, the response to a low fat diet and pancreatic enzyme supplementation, are strongly suggestive of the diagnosis of a selective pancreatic lipase deficiency in this patient.

In humans, diagnosis of isolated pancreatic lipase deficiency usually is made on the basis of low or absent intraduodenal lipase activity after stimulation with pancreozymin-secretin.3–8,l A measurement of intraduodenal lipase activity may have substantiated the diagnosis but was not possible in the present case. Also, little data are available concerning the use of the pancreozymin-secretin stimulation test in dogs. This test only determines the functional absence or presence of lipases in general and not pancreatic lipase specifically.

In humans, even in the absence of pancreatic lipase, more than 50% of dietary fat is absorbed, a finding that has been attributed to the action of other lipases (eg, gastric lipase, bacterial lipases).l For this reason, selective pancreatic lipase deficiency can be confirmed in humans by immunologic means.4,7 The absence of immunologically active pancreatic lipase suggests either that pancreatic lipase is absent or that there is a structural change that affects immunogenicity and possibly, function.7 In dogs, cPLI is believed to offer the advantages of being organ specific.9,11 Measurement of lipase activity in pancreatic tissue or measurement of serum cPLI concentration after stimulation with pancreozymin potentially could have facilitated the diagnosis in this dog, but there are no established reference ranges for these tests in dogs.

Isolated pancreatic lipase deficiency in human patients is usually, but not always, accompanied by normal duodenal activities of trypsin and amylase.9 In this dog, serum cTLI concentrations were normal, suggesting that synthesis of trypsinogen was not affected. The existence of isolated amylase deficiency in humans is controversial.7 A pancreas-specific isoenzyme of canine amylase is unlikely to exist, based on results of amylase measurements in dogs with acinar atrophy and in pancreatec-

Pancreatic Lipase Deficiency

tomized dogs.12–14 As a result, determination of the ability of the pancreas to produce amylase was not evaluated, and a defect in amylase production in this dog cannot be excluded. Measurement of duodenal amylase activity may have helped exclude this defect but it was not possible in the present case.

Unlike humans, in whom isolated pancreatic lipase deficiency rarely is accompanied by malnutrition, poor body condition was evident in the dog described here.3,5 In humans, other lipases (eg, gastric lipase) may provide intraluminal lipase activity that partially compensates for the deficiency of pancreatic lipase and prevents malnutrition.7 However, dogs might not be able to compensate for pancreatic lipase deficiency, because no increase was noted in serum gastric lipase concentrations in dogs with EPI.15 This possibility may have been the cause of the poor body condition in the dog of this report. In addition, poor body condition may have been associated with concurrent amylase deficiency or small intestinal disease.

A diagnosis of isolated pancreatic lipase deficiency was further supported by the fact that many other causes of chronic diarrhea were ruled out or seemed to be highly unlikely. Parasitic causes of chronic diarrhea were unlikely based on negative fecal examinations and repeated antiparasitic therapy. Chronic diarrhea due to enteric bacterial pathogens was unlikely because these usually cause large bowel diarrhea (often with blood), vomiting, and systemic manifestations such as anorexia and fever, whereas weight loss is not commonly noted.16 In addition, trial antibiotic therapy only temporarily eliminated the clinical signs. Maldigestion as a result of classical EPI was ruled out based on 2 normal cTLI results.

Small intestinal bacterial overgrowth, a potential cause of diarrhea and poor body condition, may occur as a primary disease or may develop secondary to other disorders including EPI.17 It is not known whether SIBO can be the result of mono-enzymatic EPI such as isolated pancreatic lipase deficiency. An increased serum folate concentration supports the diagnosis of SIBO but does not differentiate between primary and secondary SIBO. In the dog of this report, the transient response to 1 antibiotic potentially is consistent with SIBO, and a therapeutic trial with other antibiotics might have produced a better or longer lasting clinical response. The dog’s response to diet change and pancreatic enzyme supplementation suggests that either SIBO was not present or that it occurred secondary to the isolated pancreatic lipase deficiency and resolved after pancreatic enzyme supplementation. In support of the latter explanation is the evidence of hypercellularity in this dog’s small intestinal mucosa, which might have been the result of SIBO.18,19 Although mild to moderate lymphocytic-plasmacytic and eosinophilic inflammation of the small intestine was evident on histopathology, these findings were considered to be a secondary condition, rather than the primary problem. Criteria for histopathologic evaluation of infiltrative intestinal disease and its relationship to the extent of clinical signs have not yet been

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standardized in dogs, and histopathologic evidence of inflammation is not necessarily associated with clinical disease.20,21 In addition, considerable interobserver variation exists for histopathologic evaluation of intestinal tissues from dogs and cats.22 The number of inflammatory cells is not the only (and may not even be the most important) factor when evaluating an intestinal biopsy, and other factors such as villus atrophy, mucosal architectural disruption, and epithelial immaturity also are important.20 In this dog, no histopathologic abnormalities were found other than hypercellularity of the mucosa. Thus, it is unlikely that intestinal inflammation was the cause of the diarrhea, especially considering that the dog responded completely to pancreatic enzyme supplementation.

In summary, diagnosis of pancreatic lipase deficiency in the dog of this report was based on history, clinical findings, exclusion of other diseases, and undetectable serum cPLI concentration with normal serum cTLI concentration.

Footnotes a

Drontal Plus, tablets, Bayer Corporation, Pittsburgh, PA Flagyl, 250 mg tablets, Rhone-Poulenc Rorer Inc, Collegeville, PA c Amoxidrops, 50 mg per mL, Pfizer Animal Health Inc, Exton, PA d Albon, 50 mg per mL, Pfizer Animal Health Inc, Exton, PA e Prednisone, 10 mg tablets, West-Ward Pharmaceutical Corp, Eatontown, NJ f Science Diet Puppy Original, Hill’s Pet Nutrition Inc, Topeka, KS g Prescription Diet Canine i/d, Hill’s Pet Nutrition Inc, Topeka, KS h Spec cPL, IDEXX Laboratories Inc, Westbrook, ME i Prescription Diet Canine r/d, Hill’s Pet Nutrition Inc, Topeka, KS j Viokase, powder, Axcan Pharma, Birmingham, AL k Canine Potato and Venison Formula Large Breed, Royal Canin Veterinary Diet, Royal Canin USA Inc, St Charles, MO l Muller DPR, McCollum JPK, Trompeter RS, Harries JT. Studies on the mechanism of fat absorption in congenital isolated lipase deficiency. Gut 1975;16:838 (abstract) b

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