Juvenile Diabetes Mellitus and Concurrent Exocrine Pancreatic Insufficiency in a Labrador Retriever: Long-Term Management
A 3 mo old, female, entire Labrador retriever presented with vomiting, diarrhea, polyuria, polydipsia, polyphagia, and stunted growth. Diagnostics revealed the presence of juvenile diabetes mellitus and concurrent exocrine pancreatic insufficiency. Pancreatic histopathology showed severe pancreatic atrophy. Successful treatment was achieved with a combination of insulin and pancreatic enzymes. This report describes successful long-term treatment of juvenile diabetes mellitus and concurrent exocrine pancreatic insufficiency in a dog.
Introduction
Juvenile diabetes mellitus (DM) and concurrent exocrine pancreatic insufficiency (EPI) have been anecdotally reported in the literature,1–4 but all previous published reports have had fatal outcomes, as the dogs died or were euthanized due to complications or high costs associated with treatment.
Possible causes of juvenile DM are viral infections, congenital hypoplasia or immune-mediated destruction of beta pancreatic cells.5,6 Genetic predispositions for the development of canine DM have been suggested in certain breeds.7 Interestingly, studies have shown that Labrador Retrievers have a low predisposition to develop DM and EPI.7,8
Pancreatic acinar atrophy (PAA) is the most common cause of EPI in the juvenile dog.9–12 Recent studies performed in German shepherd dogs and rough-coated collie dogs suggest that the disease might be autoimmune in origin.11–13 PAA was believed to be inherited in an autosomal, recessive fashion until results from a mating test performed in 2010 disqualified this theory and suggested a polygenic mode of inheritance.13,14
Case Report
A 3 mo old, female, entire Labrador retriever was presented with vomiting, chronic diarrhea, polyuria, polydipsia, polyphagia, and stunted growth. The puppy had been purchased from a breeder 3 wk prior, and the rest of the litter was reported to be healthy. The characteristics of the diarrhea were consistent with small bowel diarrhea. On presentation, physical examination showed lethargy, moderate dehydration (7%), cachexia, and stunted growth (Figure 1). Differential diagnoses were considered for three separate conditions: polyuria and polydipsia, stunted growth, and chronic diarrhea.
Citation: Journal of the American Animal Hospital Association 51, 6; 10.5326/JAAHA-MS-6283
Blood and urine were obtained for a baseline analysis. Hematology was unremarkable. Serum biochemistry profile showed alanine aminotransferase 400 IU/L (reference interval [RI]: 8–75), alkaline phosphatase 677 IU/L (RI: 46–377), blood urea nitrogen 6.0 mg/dL (RI: 7.0–29.0), creatinine 0.7 mg/dL (RI: 0.3–1.2), glucose 489 mg/dL (RI: 60.0–118), total protein 5.0 g/dL (RI: 4.8–8.0), albumin 2.1 g/dL (RI: 2.1–3.6), and ammonium 64.71 μg/dL (RI: 0–168.60). Venous blood gases were measured and revealed mild metabolic acidosis (pH 7.3 [RI 7.31–7.42], bicarbonate 15.8 mEq/L [RI 20.0–29.0], and pCO2 35 mmHg [RI 32.0–49.0]). Serum electrolytes, including sodium, potassium, chloride, and ionized calcium, were within normal limits. Urine analysis showed specific gravity 1.036, glucosuria, and ketonuria. A diagnosis of diabetic ketoacidosis was made. Treatment was started with fluid therapy and a constant-rate infusion of regular crystalline insulina. Diabetic ketoacidosis was treated successfully, and a porcine lente insulinb was started at 0.5 IU/kg subcutaneously (SC) q 12 hr.
To investigate the possible causes of small bowel chronic diarrhea and stunted growth, an extended biochemistry profile was submitted and showed the following: trypsin-like immunoreactivity 1.71 μg/L (RI: 5–35), cobalamine 295 ng/L (RI: 275–590), folate 5.6 ng/mL (RI: 8.2–13.5), thyroxine (T4) 2.3 μg/dl (RI: 1.6–5.0), cortisol 2.8 μg/dL (RI: 2–10), and insulin-like growth factor 1 (IGF-1) 57.3 ng/mL (RI: 200–800). Bile acid stimulation test and adrenocorticotropic hormone (ACTH) stimulation test were performed at a later point and showed the following: pre-prandial bile acids 0.4 μg/mL (RI 0.0–6.2), post-prandial bile acids 0.57 μg/mL (RI 0.0–6.2) and cortisol post-ACTH 10.2 μg/dL (5.4–19.9). A zinc sulfate flotation test and a fresh fecal smear were performed and were negative for gastrointestinal parasites; parvovirus testing was negative using an ELISA commercial testc. On abdominal ultrasound, the pancreas could not be identified, but the rest of the organs were remarkably normal. Echocardiography did not reveal any abnormalities. EPI was diagnosed concurrently with insulin-dependent, or type 1, DM. A highly digestible foodd was chosen and supplemented with enteric-coated pancreatic enzymese at the doses recommended by the manufacturer. Glucose monitoring was continued at home with a portable glucose analyzerf. Blood glucose (BG) curves performed at home after discharge from the hospital showed a rapid decrease in BG and uneven glycemic control. The porcine lente insulinb was stopped, and a neutral protamine Hagedorn (NPH) insuling was started at a dose of 0.25 IU/kg SC q 12 hr, which resulted in significant improvement in the next BG curves.
At 4 mo of age, due to development of cataracts, the patient underwent bilateral phacoemulsification and two 12 mm intraocular lenses were implanted. The outcome of the surgery was satisfactory, and the puppy recovered vision shortly after the procedure. Four months later, another ophthalmological surgery was needed because of acute lens-induced uveitis as a result of growth of residual lens fibers. The residual fibers were aspirated, and under the same anesthesia, an ovariohysterectomy was performed and a pancreatic biopsy was obtained.
Macroscopically, the pancreas was small and lacked a normal parenchyma. Histology showed minimal presence of exocrine pancreatic lobules, with an insignificant amount of Langerhans islet cells; the rest of the parenchyma was replaced by adipose tissue. The number of pancreatic ducts was appropriate, and there was no ascending inflammation within the ducts. Minimal inflammation was present in the form of multifocal lymphoplasmacytic follicles (Figures 2, 3). The histological diagnosis was consistent with severe and diffuse pancreatic atrophy.
Citation: Journal of the American Animal Hospital Association 51, 6; 10.5326/JAAHA-MS-6283
Citation: Journal of the American Animal Hospital Association 51, 6; 10.5326/JAAHA-MS-6283
A few months after surgery, the dog started suffering from hypoglycemic episodes during the period of peak insulin activity, which coincided with exercise. These incidents resolved by changing the insulin, from human NPHg to porcine lenteb again, and by adding a small meal around the time of the first peak of action of the lente insulin. DM and EPI were monitored with regular physical examinations, BG curves, and fructosamine and cobalamin measurements. Fructosamine concentrations were markedly variable during the growth of the puppy, ranging from 450 to 573 mmol/L (RI 160–350), indicating poor control of the DM. Once growth was finished, BG curves improved considerably. The best stool consistency was obtained when the highly digestible food was incubated with the pancreatic enzymes and warm water for about 20 minutes in the food bowl. In an attempt to improve glycemic control, a commercial diet specially formulated for diabetic dogsh was gradually introduced as a trial for 2 mo. The new diet produced weight loss and worsened the stool consistency; hence, it was stopped and the highly digestible dietd was reintroduced. Cobalamin deficiency was detected occasionally and treated as needed with weekly injections of 0.5 mg of cobalamin SC for 6 wk, followed by 0.25 mg every fortnight for 6 mo. The patient has suffered occasional episodes of vomiting and diarrhea that failed to respond to an increase in the dose of pancreatic enzymes but resolved when ampicillini 20 mg/kg q 8 hr was added for 2 wk.
Three years after the diagnosis, the patient's condition is still being managed satisfactorily, and she has a good quality of life, although she is small for a dog of her age, sex, and breed (Figure 4).
Citation: Journal of the American Animal Hospital Association 51, 6; 10.5326/JAAHA-MS-6283
Discussion
All previously reported cases of juvenile DM have been insulin-dependent, or type 1.5 Non–insulin-dependent DM is extremely uncommon in dogs.7 Based on this fact and the absence of any disorder producing insulin antagonism, type 1 DM was thought to be most likely in this case, although it was not confirmed because baseline insulin concentrations were not measured.
The patient described in this report showed failure to grow; this can be explained by the simultaneous presence of DM and EPI. Insulin plays a major role in growth because of regulation of carbohydrate metabolism, synergistic action with growth hormone, stimulation of protein synthesis, and inhibition of protein catabolism.15,16 In addition to that, deficient nutrient intake because of the maldigestion–malabsorption syndrome caused by EPI contributes to the lack of growth. Other potential causes of stunted growth are cardiac abnormalities, hepatic abnormalities, renal disease, and juvenile endocrine disorders such as hypothyroidism, hypoadrenocorticism, hyperadrenocorticism, and pituitary dwarfism.5,17 Because there were no skeletal abnormalities, congenital chondrodystrophy was not considered. Cardiac problems were ruled out with echocardiography. Postosystemic shunts and other hepatic abnormalities were considered unlikely based on a normal bile acid stimulation test, normal ammonium concentration, and absence of abnormalities during ultrasonographic evaluation of the abdomen. Renal disease was ruled out with serum biochemistry, urinalysis, and abdominal ultrasound. A normal T4 concentration ruled out hypothyroidism. Juvenile hypoadrenocorticism and juvenile hyperadrenocorticism were ruled out by an ACTH stimulation test within RI and the normal size of both adrenal glands on abdominal ultrasound. To rule out hyposomatotropism, growth hormone deficiency has to be documented based upon the results of a stimulation test. Diagnostic imaging (CT or MRI) of the pituitary area have also been recommended. These tests were not performed in our patient, as pituitary dwarfism was thought to be unlikely because of lack of compatible clinical signs, apart from stunted growth. Dogs with pituitary dwarfism are reported to have a dull mentation, retention of secondary hairs, alopecia, and renal abnormalities manifested with an increase in serum creatinine, unlike our patient. Typically, untreated patients deteriorate rapidly and have multiple complications as a result of the disease. IGF-1 has low specificity for the diagnosis of pituitary dwarfism.16,18 The decrease in IGF-1 in our patient could be explained by the lack of insulin, as human studies suggest that insulin stimulates the synthesis of IGF-1 in the liver.19 A decrease in IGF-1 was also found in a dog with juvenile DM and concurrent EPI.2
Previous recommendations for insulin treatment in juvenile DM included a combination of porcine lente insulin q 12 hr with the administration of regular insulin after each meal.5 In this case, we decided not to follow that approach, as there were no severe postprandial hyperglycemic episodes that could justify the use of regular insulin. Human NPH insulin was chosen during growth for its gradual lowering of BG compared to porcine lente insulin. Hypoglycemic episodes presented after the second surgery were related to an increase in exercise. Human NPH insulin was discontinued and the porcine lente was initiated again alongside the addition of a small meal given at the period of peak insulin activity. These changes produced optimal BG curves and allowed the animal to exercise without causing clinical hypoglycemia.
The best stool consistency was achieved when the capsules containing the pancreatic enzymes were opened, mixed with the food and warm water, and then incubated for 20 min. There is no agreement regarding this procedure in the literature.9,11 A recent prospective, blinded, randomized study demonstrated that dogs receiving enteric-coated pancreatic enzymes responded better to treatment.20
Similarly to another published report, our patient developed diabetic cataracts rapidly.2 The rapid progression of the cataracts could be explained by the uneven glycemic control during the puppy's growth. Lens-induced uveitis is a common complication following cataract surgery. It happens as residual lens epithelial cells produce more new lens fibers and is more common in young dogs.21
The puppy suffered from intermittent episodes of vomiting and diarrhea, possibly as a result of small intestinal bacterial overgrowth (SIBO). In some animals, there is a positive response to increasing the amount of pancreatic enzymes administered. However, SIBO is common in dogs with EPI before and after enzyme replacement. Antibiotics are needed when there is a poor response to enzymes alone or when clinical signs of poor digestion are present.9 Antibiotics commonly used to treat this condition are tylosin, oxytetracycline, or metronidazole. In our case, neither an increase in the dose of pancreatic enzymes nor the addition of metronidazole or oxytetracycline produced clinical improvement; only the addition of ampicillin controlled the clinical signs and improved the fecal consistency. Although not described for treating this condition, ampicilin was chosen based on its broad-spectrum antimicrobial activity, drug availability, and affordable cost rather than on proven efficacy treating SIBO.
The pancreatic histopathology of this case is similar to previous published reports, as it showed fatty infiltration of the parenchyma, the existence of lymphoplasmacytic inflammation, and normal pancreatic ducts.1–3At a first glance, the presence of pancreatic ducts appeared to be increased due to the reduction in the amount of parenchyma tissue. A more detailed examination revealed normal number and morphology of ducts. The cause for the concurrence of juvenile DM and EPI in this dog remains unclear.
Given the early age of presentation of EPI and DM , one of our differential diagnoses at the time of presentation was pancreatic hypoplasia. However, the scarce presence of inflammation suggests a chronic destructive process rather than a hypoplastic one.22
Conclusion
This case report shows that juvenile DM with concurrent EPI can be treated successfully in dogs, and, although management can be challenging and associated costs are high, good quality of life can be achieved.
Patient at 3 mo of age (on the right-hand side) sitting next to an age-matched, normal Labrador retriever to illustrate the stunted growth.
(5x). Pancreas. Hematoxylin and eosin stain. There is a severe and diffuse acinar atrophy replaced by abundant adipose tissue. There are some remnant lobules of exocrine parenchyma where small lymphoid follicles can be observed (arrows).
(10x). Pancreas. Hematoxylin and eosin stain. Within the remnant lobules of exocrine parenchyma, there are few acinar structures (long black arrow) with abundant smaller ducts (small black arrow) and lymphoplasmacytic infiltration, forming a lymphoid follicle (arrow head).
Comparison of adult sizes. Patient 4 yr after the diagnosis of DM and EPI (on the right-hand side) sitting next to a healthy, 4 yr old, female Labrador retriever (left-hand side).
Contributor Notes
