A 21-year-old neutered male adult California sea lion (Zalophus californianus) was housed at the Mystic Aquarium and Institute for Exploration with 3 other male California sea lions for 6 years. This sea lion was originally obtained from the wild as a yearling and had lived for 14 years at another facility in an environment that allowed access to ocean water and wild fish; however, prophylactic administration of anthelmintics, including ivermectin and praziquantal, was routinely performed.
At the time of the sea lion's arrival in June 2001, a CBC and serum biochemical profile revealed no abnormal findings. Recognized existing health problems included chronic recurrent nonulcerative keratopathy and immature bilateral cataracts. During the next 3 years, the sea lion had only minor clinical problems, including a corneal ulcer, dermatologic lesions, and intermittent gastrointestinal disturbances. Results of CBCs and serum biochemical analyses collected during routine procedures during the sea lion's first 3 years of residence were within reference ranges.
Beginning in May 2004, increased serum cholesterol (669 mg/dL; reference range, 165 to 507 mg/dL1) and triglyceride (1,086 mg/dL; reference range, 74 to 110 mg/dL2) concentrations were detected. A subsequent serum sample collected in January 2005 revealed lipemia, hypertriglyceridemia (584 mg/dL), hypercholesterolemia (648 mg/dL), and the first appearance of hyperglycemia (307 mg/dL; reference range, 70 to 203 mg/dL1). Hyperglycemia was initially attributed to stress secondary to squeeze-cage restraint and handling. However, follow-up blood samples collected in February 2005 confirmed the chronically increased serum triglyceride (1,281 mg/dL), cholesterol (766 mg/dL), and glucose (404 mg/dL) concentrations. Evaluation of a free-catch urine sample at that time revealed severe glucosuria (2,000 mg/dL; reference range, negativea) as measured with a urine test strip.b
Concurrently, in January 2005, the sea lion began to have persistent polyphagia, polyuria, and polydipsia; frequent episodes of gastrointestinal upset; and progression of the lenticular cataracts from immature to mature. During the episodes of gastrointestinal upset, the sea lion had anorexia; lethargy; signs of abdominal discomfort, characterized by an arched abdominal posture and tucked fore and hind flippers; vomiting; diarrhea and steatorrhea; and icteric mucous membranes. Marked increases of serum bilirubin concentration (4.5 to 6.5 mg/dL; reference range, 0.1 to 0.4 mg/dL1) and J-glutamyl transferase activity (685 to 1,832 U/L; reference range, 20 to 103 U/L1) were also observed. These episodes occurred 3 to 5 times/y with duration varying from 1 to 4 weeks. Between these episodes, the sea lion appeared healthy and the J-glutamyl transferase activity and bilirubin concentration were within reference ranges.
The transient nature of the gastrointestinal episodes and serum biochemical abnormalities consistent with cholestasis, combined with persistent hyperglycemia, were strongly suggestive of pancreatitis with hepatobiliary involvement and secondary diabetes mellitus. Differential etiologies for underlying or concurrent problems included pancreatic, hepatic, biliary, or intestinal neoplasia; parasitism; nutritional imbalances; hyperadrenocorticism; thyroid disease; or inflammatory bowel disease.
Multiple fecal samples were evaluated via direct smear and sodium nitrate flotation techniques, and no parasite eggs, larvae, or adults were identified. The urine cortisol-to-creatinine ratio was determined in August 2005 and in January 2007 and found to be 14 and 42, respectively (a value > 13 is consistent with but not diagnostic for canine hyperadrenocorticismc). Although the ratio increased over time, the urine cortisol concentration declined, greatly reducing the likelihood of hyperadrenocorticism. Frequent urinalysis and bacteriologic culture of urine were performed and revealed no evidence of concurrent urinary tract disease.
Thyroid function was evaluated, including serum total thyroxine (0.49 μg/dL), free thyroxine (0.618 ng/dL), and thyroid-stimulating hormone (0.178 ng/mL) concentrations. Serum total thyroxine, free thyroxine, and thyroid-stimulating hormone concentrations were also measured in a healthy sea lion from the same captive environment for comparison and were 1.15 μg/dL, 1.1 ng/dL, and 0.132 ng/mL, respectively. Although the values were lower in the affected sea lion than in the healthy control sea lion, they did not fit the pattern of hypothyroidism and were interpreted to be associated with concurrent illness (ie, euthyroid sick syndrome), which commonly leads to lower baseline thyroid hormone concentrations in dogs.3
Serum fructosamine concentration was measured before the onset of disease (179 μmol/L; reference range, < 450 μmol/L [an indication of good regulation in dogs and catsc]) and prior to insulin administration (351 μmol/L). Although values typically increased, all were within canine and feline reference ranges. Serum insulin concentrations were measured in archived serum samples collected before the onset of hyperglycemia (< 1.2 μU/mL; reference range, 5 to 20 μU/mL in dogs and catsc), shortly after the onset of insulin administration (4.9 μU/mL), and during the course of insulin administration (17.6 μU/mL).
Abdominal ultrasonography was performed by a board-certified veterinary radiologist. The liver, kidney, spleen, urinary bladder, adrenal glands, and intestinal tract had normal echogenicity and structure. There was moderate diffuse thickening of the entire wall of the gallbladder, but no distention, sludge, or choleliths were identified. The right limb of the pancreas was abnormally thin, but evidence of inflammation or fibrosis was not identified. Anatomically and ultrasonographically, the abdominal organs of sea lions are quite similar to those of dogs; therefore, the findings from this evaluation were compared with those of sea lions and dogs as reference species.
Because of lack of diagnostic evidence for other etiologies, a clinical diagnosis of chronic relapsing pancreatitis with secondary diabetes mellitus was made. This diagnosis presented several challenges, including the need to monitor blood and urine glucose concentrations and administer injectable insulin at least once a day in an animal of a species for which there is limited understanding of glucose and insulin regulation and in which effects of insulin administration had not been reported.
Initially, in August 2005, the sea lion was maintained in a large cage so that monitoring, treatments, and training for behavioral monitoring could begin at the same time. Because the dose and response to treatment were completely unknown in this species, a conservative dose of neutral protamine Hagedornd insulin (0.35 U/kg [0.16 U/lb], IM, q 24 h) was administered. The insulin was administered with a 1-inch, 25-gauge needle in the caudal portion of the gluteal muscles, an area with low muscle thickness where a needle of this size would dependably reach muscle tissue.
Blood glucose concentrations obtained by use of a glucometere designed for humans were measured twice daily by collecting a small amount of blood from the distal end of a hind flipper digit with a 25-gauge needle. The first blood glucose measurement was a preinsulin administration value (or approx 24 hours after insulin administration), and the second value was obtained approximately 6 hours after insulin administration (Figure 1). Additionally, urine glucose concentrations and additional urine analyte values were obtained by use of urine test strips.b After 6 days of safely administering neutral protamine Hagedorn insulin once daily, the frequency was increased to twice-daily injections at the same dose. During the initial few weeks, glycemic control ranged from fair to good. The sea lion was still housed in a cage and had no overt signs of disease or complications associated with insulin administration.
Blood glucose concentrations in a sea lion with diabetes mellitus before (gray bars) and 6 hours after (black bars) administration of neutral protamine Hagedorn (NPH) insulin once daily at various doses (days 1 and 2, 50 units; days 3 and 4, 60 units; and days 5 and 6, 63 units) over a 6-day period.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1707
In September 2005, administration of glarginef insulin was initiated. Glargine insulin, a human synthetic insulin analog produced by recombinant DNA technology, has the longest duration of action in humans and has been effectively used to treat human and feline diabetics with once-daily injections, which was desirable in this sea lion.4–7 Beginning at 0.5 U/kg (0.23 U/lb, IM, q 24 h), the insulin dosage was increased to 0.75 U/kg (0.34 U/lb, IM, q 24 h) on the basis of the previous day's responses. Administration of this dosage resulted in serum glucose concentrations within reference range 6 hours after administration (Figure 2) with reduced glucosuria or absence of glucosuria. To facilitate longterm management of the sea lion's condition in a more normal routine, caging was discontinued, and insulin administration was stopped for 3 months to train the sea lion to voluntarily allow blood sampling and insulin administration.
During episodes of pancreatitis, the sea lion's response to insulin became inconsistent and the sea lion would be either more sensitive to or less dependent on exogenous insulin (ie, intermittent periods of glucose autoregulation lasting a few weeks to a month). A mild hypoglycemic event consisting of signs of depression and mild seizure activity quickly eliminated by oral and rectal administration of glucose occurred during such an episode. During these episodes, the sea lion often became anorexic, making it difficult to collect blood for glucose analyses via food-motivated behavioral means, so monitoring the effects of insulin administration was hampered. Insulin administration often had to be discontinued during these periods of illness.
Blood glucose concentrations in the same sea lion as in Figure 1 before (gray bars) and 6 hours after (black bars) administration of glargine insulin once daily at various doses (day 1, 70 units; day 2, 77 units; day 3, 85 units; day 4, 92 units; day 5, 98 units; and day 6, 105 units) over a 6-day period.
Citation: Journal of the American Veterinary Medical Association 232, 11; 10.2460/javma.232.11.1707
The sea lion's condition was medically managed for approximately 1.5 years. Blood and urine glucose concentrations were monitored daily. During once-daily glargine insulin administration, blood glucose regulation ranged from fair to good; however, mild glucosuria most often persisted. Insulin administration diminished but did not eliminate the clinical signs associated with diabetes mellitus. Pancreatitis was managed via daily administration of prophylactic antimicrobials and gastrointestinal protectants, which included metronidazole (10 mg/kg [4.5 mg/lb], PO, q 12 h) and ranitidine (1 mg/kg [0.45 mg/lb], PO, q 12 h). For nutritional management of pancreatitis in dogs and cats, it is recommended that patients receive a low-fat diet.8 The typical diet for sea lions at this facility consisted of a variety of fish including herring, capelin, and squid. The sea lion's diet was restricted to an all-capelin diet, the available fish with the lowest lipid content, to meet these nutritional recommendations for managing pancreatitis.
During the episodes of illness, various analgesic, antiemetic, and antidiarrheal medications were administered. Prophylactic antimicrobials, typically a fluoroquinolone, were also administered during illness, on the basis of the typical bacterial flora, primarily gram-negative organisms, that are identified in association with pancreatic and hepatobiliary diseases.8 When evidence of cholestatic disease was identified, ursodeoxycholic acid,g a choleretic agent, was administered (10 mg/kg [4.55 mg/lb], PO, q 24 h). Episodes of pancreatitis still occurred; however, the overall frequency and severity of associated clinical signs decreased. Outside of the brief periods of illness, the sea lion was active and alert with a good appetite and normal feces.
In April 2007, the sea lion developed a severe illness and died a few days later. During this illness, the sea lion developed ketonuria in addition to serum biochemical abnormalities, which suggested the development of diabetic ketoacidosis. A CBC revealed moderate leukopenia (2,300 WBCs/μL; reference range, 3,400 to 11,380 WBCs/μL1) with a degenerative left shift and toxic neutrophils (828 band neutrophils/μL; reference range, 0 to 10 band neutrophils/μL1). Abdominal ultrasonography conducted the day of the sea lion's death revealed severe distension of the gallbladder and bile ducts.
A necropsy was performed. The pancreas was effaced by fibrosis, with adhesions to the ileum, duodenum, root of the mesentery, and mesenteric lymph nodes. The surface of the pancreas had numerous, thick-walled, raised, 0.5- to 2-cm-diameter abscesses protruding from the surface and present throughout the parenchyma that contained thick, yellow-tan or brown, granular material. Mesenteric and pancreatic lymph nodes were enlarged and edematous. The intrahepatic biliary tree was dilated and prominent. The gallbladder was markedly enlarged, thin-walled, and filled with bile. Cystic, hepatic, and common bile ducts were also dilated. Peripancreatic fibrosis surrounded and constricted the distal portion of the extramural bile duct, although the bile duct was patent. In the subcutaneous tissue of the neck and body, there were multiple, 1- to 3-cm-diameter X 3-mm-thick, irregularly round, flat fibrous nodules. Hemolytic Streptococcus agalactiae was cultured from swab specimens and sections of pancreatic tissue. Microbiologic culture of the bile yielded negative results. Examination of the thyroid, adrenal, and pituitary glands did not reveal any abnormal gross or histologic findings.
Histologic examination revealed severe, chronic fibrosing suppurative pancreatitis with exocrine and endocrine atrophy and abscesses arising from ectatic pancreatic ducts filled by necrotic debris. There was mild proliferative and lymphoplasmacytic choledochitis. Subcutaneous nodules were found to be foci of granulomatous steatitis attributed to metastatic fat necrosis, which is described as a complication of pancreatitis in humans and cats.9,10
Discussion
The gross and histopathologic findings confirmed the antemortem diagnosis of primary chronic pancreatitis leading to secondary diabetes mellitus and intermittent cholestasis. To our knowledge, this is the first report of pancreatitis and secondary diabetes mellitus and insulin treatment in a pinniped.
The reported prevalence of pancreatic disease in pinnipeds is extremely low, and pancreatic disease is often associated with neoplasia or parasitism. Pancreatitis associated with a gallstone was reported in a Hawaiian monk seal (Monachus schauinslandi).11 Fibrosing pancreatitis, bile duct fibrosis, chronic cholangitis, and gastric ulceration have also been associated with trematodes from the Campulidae family in a bearded seal (Erignathus barbatus).12 Liver flukes (Zalophatrema hepaticum) have been identified in free-ranging California sea lions (Z californianus) and Steller's sea lions (Eumetopias jubata) and frequently inhabit the hepatobiliary and pancreatic systems, often causing gross and histopathologic changes.13–15 Fauquier et al16 reported a case of a biliary adenocarcinoma with metastasis to the pancreas in a stranded Northern elephant seal (Mirounga angustirostris). Also, a pancreatic duct adenoma with secondary intestinal strangulation was identified in a captive California sea lion.17
The pathogenesis of pancreatitis in humans, dogs, and cats is complex and poorly understood, and the disease often appears to be idiopathic. Risk factors associated with pancreatitis in humans, dogs, and cats include trauma (ie, physical or surgical trauma), hypoperfusion, neoplasia, pharmaceutical agents, infectious agents (ie, Toxoplasma gondii, liver flukes, and feline infectious peritonitis virus in cats; Mycoplasma spp and flukes in humans), hereditary factors (ie, hereditary pancreatitis in humans and Miniature Schnauzers), endocrinopathies (ie, diabetes mellitus, hypothyroidism, and hyperadrenocorticism), nutritional factors, and hypertriglyceridemia.18,19
A diagnosis of pancreatitis in veterinary species can be challenging and should be based on a combination of clinical, etiologic, and histopathologic features, when available.8,18,20 Diagnostic modalities used in human, canine, and feline medicine include abdominal ultrasonography and radiography, abdominal computed tomography, pancreatic biopsy, and specialized pancreatic serum assays. The serum assays available for dogs and cats measure serum pancreatic lipase immunoreactivity.21,22 These tests are noninvasive and highly sensitive and specific for detecting pancreatitis, but are presently not available for marine mammals. A histopathologic diagnosis of pancreatitis in surgical biopsy specimens has traditionally been the gold standard. However, results of a recent study23 revealed that histopathologic lesions of pancreatitis in dogs can be highly localized and may be missed in a single biopsy specimen.
Early in the course of disease in the sea lion reported here, high serum triglyceride and cholesterol concentrations combined with clinical signs were suggestive of pancreatitis and were detected prior to the onset of hyperglycemia and clinical signs of diabetes mellitus. Ultrasonographic evaluation did not identify active pancreatic inflammation; however, abdominal ultrasonography may lack sensitivity in humans and small animals with pancreatitis, and normal findings cannot rule out disease.24–26 Because of the surgical and anesthetic risks associated with this sea lion's condition, surgical biopsy was not attempted.
In humans, dogs, and cats, concurrent inflammatory conditions of the liver, pancreas, and intestinal tract occur commonly. Whether this phenomenon is simply related to the close anatomic proximity of these organs or attributable to their functional relationship has not been determined.8,27–30 In the case reported here, the sea lion had clinical and hematologic evidence of cholestasis during the periods of pancreatitis, which were later found to be caused by fibrosis around the common bile duct, leading to partial biliary obstruction and marked distension of the gallbladder. Exocrine pancreatic atrophy, which had been suspected during episodes of pancreatitis with steatorrhea and weight loss, was also diagnosed postmortem. The suspected exocrine impairment was transient because abnormal feces were only observed during episodes of disease.
The etiology of diabetes mellitus in humans and small animals is thought to be multifactorial and may involve genetic predisposition, infection, insulin-antagonism, drugs, obesity, and pancreatitis.31 As was likely in the sea lion reported here, chronic pancreatitis, through fibrosis and atrophy, can lead to loss of endocrine pancreatic tissue, varying degrees of β-cell function impairment, loss of insulin production, impaired glucose transport, and altered hepatic gluconeogenesis and glycogenolysis. These sequelae often develop in humans and cats, and diabetes mellitus can be transient, depending on the degree of active inflammation.27,30,32
Although multiple studies have increased our understanding of glucose regulation in pinnipeds, many of the regulatory mechanisms involved in gluconeogenesis and response to insulin remain unknown in this species. Pinnipeds have a diet that is low or lacking in carbohydrates, and it has been suggested that pinnipeds rely less on insulin and more on gluconeogenesis to maintain glucose homeostasis.33–36 Glucose production and regulation has been investigated in wild elephant seals, diving harbor seals (Phoca vitulina), and Weddell seals (Leptonychotes weddellii), and it is presumed that gluconeogenesis is sustained via multiple factors, including use of amino acid precursors, glucose recycling via lactate utilization through the Cori cycle, and free fatty acid oxidation.34–39 Ketone body formation, specifically D-β-hydroxybutyrate, remains low after prolonged withholding of food in adult male and female elephant seals, likely because of these recycling mechanisms.37
In the sea lion of this report, stress-induced hyperglycemia and subsequent glucosuria were initially considered to be secondary to cage restraint and handling. However, because blood and urine were collected via trained behaviors in the sea lion's normal environment for nearly the last 2 years of the sea lion's life, chronic stress was considered unlikely.
Insulin concentrations have been reported in other marine mammal species, but there are no published reference ranges for California sea lions. In a diving physiology study involving harbor seals, Robin et al38 reported the predive insulin concentration range to be 4 to 12 μU/mL. In the sea lion reported here, it is difficult to draw major conclusions with regards to insulin concentrations. However, when compared with ranges for the dog, cat, and harbor seal, hypoinsulinemia appeared to be present prior to the onset of diabetes and insulin therapy appeared to maintain insulin concentration at a reasonable value. It was unknown whether the diabetes mellitus was caused by an absolute insulin deficiency or was secondary to factors that can lead to insulin resistance, such as chronic inflammation from pancreatitis. The histopathologic diagnosis of severe pancreatic fibrosis with endrocrine atrophy strongly suggested that a lack of insulin production was a major factor.
The inciting cause of pancreatitis in the sea lion reported here was unknown. No specific parasitic, neoplastic, or autoimmune etiologies were identified. However, evidence of these processes may have been obscured by the chronic inflammatory changes. Although S agalactiae was cultured from abscesses and pancreatic tissues, large numbers of gram-positive cocci were not seen in histologic sections of the pancreas. Therefore, the relevance of this finding was unknown. Nutritional or other infectious etiologies could not be ruled out. The cause of death appeared to be multifactorial. An idiopathic decrease in the sea lion's response to insulin developed during the last few months prior to death. The sea lion's aggressive behavior during this crisis limited our ability to monitor blood glucose concentrations and administer exogenous insulin. The ketonuria combined with the hematologic abnormalities were suggestive of a ketoacidotic crisis. Severe leukopenia with toxic neutrophils suggested concurrent septicemia.
Findings indicated that primary pancreatitis with secondary diabetes mellitus can develop in captive California sea lions and should be considered as a differential diagnosis in pinnipeds with similar clinical findings. Glucose regulation via once-daily administration of glargine insulin ranged from fair to good. Daily monitoring of blood and urine glucose is strongly advised during treatment.
Mystic Aquarium in-house reference range, Mystic, Conn.
Multistix 10 SG reagent test strips for urinalysis, Bayer, Ecatepec, Mexico.
Antech Diagnostics, Lake Success, NY.
NPH human insulin, Eli Lilly and Co, Indianapolis, Ind.
Accu-Chek Advantage glucometer, Roche Diagnostics, Indianapolis, Ind.
Lantus insulin (glargine), Aventis Pharmaceuticals Inc, Kansas City, Mo.
Ursodiol, Corepharma LLC, Middlesex, NJ.
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