Metabolic Diseases

Three meerkats (Suricata suricatta) from the North Carolina Zoo were diagnosed with cholesterol granulomas in 2000{4062}. The first presented with acute depression, lethargy and dehydration. Serum cholesterol was >520 mg/ml. There were severe osteolytic lesions in the dorsal calvarium, cervical and thoracic spondylosis and cardiomegaly, suggesting dilatative cardiomyopathy. The cerebrum had cholesterol clefts that even replaced overlying bone. The pericardium had a similar lesion. The second meerkat was found dead, and had valvular and ventricular endocarditis, renal cholesterol granulomas and another in the pancreas. A third presented with mandibular swelling and gingival hyperplasia (was a recurrent squamous cell carcinoma), and serum cholesterol of >300. He had a cholesterol granuloma in the spleen.

Cholesterol granulomas are considered to be benign and are usually incidental findings. Only the first case here was considered to be neoplastic. They are thought to form at sites of hemorrhage or necrosis and inflammation. Rabbits on high cholesterol diets form them in the choroid plexus, which in humans is thought to be related to high serum cholesterol and triglycerides. The meerkat diet (processed meat and dry dog food supplemented with hard boiled eggs and fresh vegetables) may have caused the problems in these animals.

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Gastrointestinal Tract

NSAID-induced gastroduodenal injury

NSAIDs are increasingly being used to control pain in laboratory animals; however there is a paucity of information about dose and frequency. In humans, dogs, rats and rabbits, NSAIDs may induce gastric and/or duodenal injury that ranges from slight inflammation to ulceration and perforation. Traditional therapies include: (1) protective agents such as bismuth subsalicylate, kaolin pectate, and sucralfate; (2) buffers such as magnesium and aluminum-based antacids; (3) H₂-receptor antagonists such as cimetidine; (4) omeprazole, a gastric proton-pump inhibitor that is highly potent in eliminating gastric acid secretion but may result in hypergastrinemia and gastric carcinoid (in rats); (5) prostaglandin E₁ analogs such as misoprostol, which are needed to restore the beneficial effects of prostaglandins on mucosal integrity such as reduced gastric acid secretion, enhanced gastric bicarbonate, mucosal blood flow, secretion of gastric mucus, and stimulation of epithelial restitution; and (6) physiologic levels of nitric oxide (NO), which has received recent attention as a mucosal epithelial protectant.

NO is released from vascular endothelium and enteric neurons. When released locally in the gastric mucosa, it inhibits acid secretion, enhances mucosal blood flow, increases mucous secretion, and enhances bicarbonate release. It also stimulates release of pro-inflammatory peptides. Paradoxically, at high local NO levels such as those produced when iNOS is induced during gastric inflammation, oxyradicals are formed which damage epithelial integrity. L-NAME (N4-nitro-L-arginine methyl ester) is an inhibitor of nitric oxide synthase (NOS). In rats, it protects the stomach and duodenum against ulcers induced by potent NSAIDS such as the experimental drug CI-987 better than misoprostol (or any of the other treatments listed above).{4085} However, L-NAME when given to miniature swine causes mean arterial blood pressure to rise significantly (more than in humans, dogs or domestic swine) and GFR decreased. The sympathetic nervous system appears to control these variables in the minipigs.{3905}

Disorders of White Blood Cells

Large Granular Lymphocytosis (LGL)

LGLs are interesting because they are tumoricidal, antiviral and immunoregulatory. They have abundant pale-staining cytoplasm with many small azurophilic granules. In humans, LGLs can be either reactive and transient, or persistent, in which case there is the potential for neoplasia. Human LGLs are either CD3^- NK cells mediating MHC-restricted cytotoxicity, or CD3⁺ cytotoxic T cells.

Little is known about canine LGLs. They are from diverse lineages and frequently express the leukointegrin a_db₂. Clinically, some dogs are more often affected (older dogs of large breeds), and disease ranges from slight to severe. The T cell receptor has been analyzed, and 60% of LGL cases had proliferations of ab T cells, but a surprisingly large proportion (32%) had proliferations of gd T cells. The rest were non-B non-T cells, maybe NK cells but the reagents for dogs don't exist yet. Canine LGL arises in the splenic red pulp. Chronic canine erhlichiosis can cause persistent gd T cell LGL.

In humans, most LGLs are leukemias, with morbidity related to cytopenia rather than a tumor. Leukemia is defined as malignant neoplasia of hematopoietic cells in the bone marrow that spill over into the blood; however in dogs the leukemia starts in the spleen. Splenic involvement is also a prominent feature of LGL leukemia in the Fischer 344 rat, in which this is a major cause of death. Affected rats show anemia, jaundice, splenomegaly, and leukocytosis of 70-180,000/ml.{4056, 4757}

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Inborn Errors of Metabolism

Maple syrup urine disease in cattle

Polled Hereford calves develop edema of the myelin sheath related to excessive levels of branched chain amino acids (leucine, isoleucine, valine) caused by lack of ketoacid decarboxylase{4105,4106}. They die soon after birth with CNS depression, lethargy, recumbency, limb extension, tremors and disorganized paddling. The urine is often noted to smell like maple syrup, caused by isoleucine. A toxic metabolite is thought to cause spongy degeneration of the white matter; the intraperiod line is widened and the myelin sheath separates or splits. This is similar to the classic human infantile type. In cattle it is autosomal recessive. Other species affected by spongy degeneration from autosomal recessive genes include dogs (Labs, Salukis, silky terrier and Samoyed), cats (Egyptian Mau) and other cattle (Jersey, Shorthorn, Angus-Shorthorn).{4105}

Bovine citrullinemia

This is an autosomal recessive disease in Friesian calves caused by deficiency of arginosuccinate synthetase. The urea cycle is affected with buildup of plasma citrulline to very high levels. In humans and calves, signs appear during the first week of life and include depression, vocalizations, opisthotonus and ending up with seizures and death. Surviving patients have impaired intellectual function. Pathologically there is cerebral edema and neuronal necrosis, although the brain appears normal grossly.{4107}

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Lysosomal storage diseases

In these diseases, material accumulates within cell lysosomes, often killing the cell. Most of the diseases result in accumulation of substrates and/or precursors. If the CNS is involved the diseases are called gangliosidoses. In humans, the most well-known gangliosidosis is Tay-Sachs disease. It is inherited as an autosomal recessive disease; homozygotes are affected but heterozygotes may be phenotypically normal but have approximately half the required enzymatic activity, a gene-dose effect. Acquired diseases are often caused by toxic plants, iron accumulation (hemosiderosis), and copper accumulation. Many lysosomal storage diseases affect the neuron, but globoid cell leukodystrophy affects the oligodendrocytes, with subsequent dysmyelination.{4105} There are several models of gangliosidosis (specifically mucopolysaccharidosis I and VII) in the dog and cat which have arisen spontaneously and reported in the Fascicles; see the animal models database for details.

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Thyroid Diseases

Goiter

Euthyroid hyperplastic goiter was diagnosed during routine health monitoring of a closed Syrian hamster colony (SG). Adult and juvenile hamsters were affected at a prevalence of 45%. Histologic examination of the enlarged thyroid gland revealed marked follicular cell hyperplasia. Because prevalence of thyroid hyperplasia in this colony exceeded the 6 to 7% prevalence expected in aged hamsters, additional studies were performed to investigate the pathogenesis of this condition. Juvenile male hamsters and age- and sex-matched Syrian hamsters that did not have increased prevalence of goiter were obtained from an unrelated source (Fredrick Cancer Research and Development Center [FCRDC]). The thyroid glands of 8/18 SG hamsters and none of the FCRDC hamsters were enlarged. Serum baseline and post-thyrotropin thyroxine were not significantly different. Diet was ruled out as the cause of goiter. A genetic cause may play a role.{3871}

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Diabetes Mellitus

Guinea pigs have been reported to develop diabetes in the laboratory setting, but there are few reports in the clinical literature. Diabetes mellitus occurs in three types: Type I (insulin-dependent) is the most common type in dogs and cats; Type II (non-insulin-dependent) occurs in cats and is managed with oral hypoglycemic agents; and Type III (hormonal induced). A case report of type II diabetes was published in 1999; the patient was an intact male guinea pig that initially responded to ultralente insulin but then became refractory. He was managed well on an oral agent, DiaBeta. PU/PD resolved, he gained weight, and glucosuria decreased. At necropsy he had terminal uremia secondary to decreased kidney function, due to an invasive tubular cyst.{4520}

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Urogenital Diseases

Chronic progressive glomerulonephropathy

This is very common in aging male Sprague-Dawley and F-344 rats, and may also be called "chronic progressive nephrosis" or just "old rat nephropathy". It may occur in up to 75% of susceptible strains with these predisposing factors: age >12 months, males, high-protein diets, mesangial IgM deposits, and high prolactin levels. Clinical signs are proteinuria, weight loss, and high creatinine consistent with renal insufficiency. In advanced cases there may be renal secondary hyperparathyroidism and mineralized deposits in several tissues. Serum cholesterol is elevated.{4208, 4757}

Hydronephrosis

The brown Norway and Gunn strains of rat commonly have hydronephrosis. In Brown Norways it is inherited as a polygenic trait with incomplete penetrance; in Gunns it is autosomal dominant and lethal in homozygotes. It is also highly heritable in Sprague-Dawley rats, as a polygenic trait. Since it usually affects the right kidney, one theory is that it is caused by passage of internal spermatic vessels across the ureter causing obstruction of flow. The defect may be fatal if bilateral.{4208, 4757}

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Hematuria/renal papillary hyperplasia

Intermittent hematuria may occur in brown Norway x Lewis rats, mostly in males. Lesions consist of renal papillary proliferative change with hemorrhage and stromal necrosis.{4208}

Nephrocalcinosis

Deposition of calcium phosphate in renal tissue is more common in female rats than males. Incidence in F-344 rats reaches 50% and may occur as young as 7 weeks of age. BDIX rats are also affected. Diet is a factor when there are high levels of calcium or phosphorus, or low magnesium.{4757}

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Respiratory system

Alveolar histocytosis is very common in old rats. Grossly it appears as tiny 1mm white or pale tan foci on the lung surface. Histologically this is clusters of alveoli with increased numbers of large, pale, foamy-appearing macrophages and sometimes cholesterol clefts. The cause is unknown. It should be differentiated from viral infectious causes.{4757}

Comments? Send an email to janet.rodgers@vet.ox.ac.uk