Ferrets (Laboratory) - Pathology

Introduction

Ferrets (Mustela putorius furo) are thought to have been dometicated for over 2000 years and are descended from the wild European Polecat. Despite being domesticated for such a long period, ferrets were only recognised as important in medical research in the 20th century and were only beginning to be used in the 1960s as an important animal model. Ferrets are often utilised in a laboratory setting as they are known to share many anatomical, metabolic and physiological features with humans. Therefore ferrets are often utilised in studies covering a broad subject matter including toxicology, bacteriological and virological studies. Ferrets have also been used as a model for studies into ischemia and ion exchange in the heart, influenza, neurological injury and gastric infections. Ferrets are particularly important in influenza studies as they can be infected with type A and B influenza viruses. According to the US Department of Agriculture Animal Care Report, approximately 17,000 ferrets were used in laboratory studies.

As ferrets are a social, curious and intelligent species, they often require a higher level of husbandry than other species such as hamsters or mice. Laboratory ferrets will require a complex and stimulating environment with enrichments that include tubes and boxes that are able to simulate a burrow. Ferrets have a strong drive to explore and therefore they will investigate all aspects of their enclosure. Enclosures therefore need to be well designed and strong as ferrets will exploit any opportunity to escape.

Strains and Stocks

Most ferrets utilised for laboratory studies are males due to oestrous related health problems associated with females. Female ferrets are induced ovulators and can develop severe hyperoestrous if not mated. Laboratory ferrets are often purchased pre-castrated and 'de-scented' (i.e. anal gland sacculectomy).

Due to the small number of laboratory ferrets compared to species such as mice, there are no specific strains/stocks commonly used. Researchers often request natural wild-type colour patterns (called sable or fitch) which is often in contrast with the various coat colour variations found in domestic populations. Some studies have also utilised albino ferrets.

Physiology

Most physiological data for ferrets is very similar to that of the domestic cat. Ferrets are obligate carnivores that typically have a total length of ~50cm (with a ~13cm tail) and weight between 0.7 - 2kg. Ferrets have a natural life span of between 7 - 10 years and males are substantially larger than females, with males up to 2kg and females up to 1.2kg. Ferrets become sexually mature at around 4-6 months and occurs in the first spring after birth.

Ferret gestation is 42 days and litters usually contain between 3-7 young. The litter are usually weaned between 3 - 6 weeks and are totally independant of the parents at 3 months. Females can have up to 3 litters annually.

Ferrets are crepuscular and therefore they spend between 14-18hrs per day asleep and are most active around dawn and dusk. Ferrets have scent glands near their anus which are used for scent marking. Ferrets have also been shown to use urine marking.

Anatomy and Histology

This section has been included to allow familiarisation with the peculiarities of ferret anatomy to provide a context for some of the disease and pathological headings found below. Therefore only anatomical areas with specific features warranting emphasis have been included below;

Digestive System

As ferrets are obligate carnivores, they require a diet containing high levels of fat and protein. High quality cat food or kitten food is commonly used. Adult ferrets also have comparatively large spleens which is often caused by extramedullary haematopoiesis, although this is non-pathogenic.

Diseases

For ease of use, the diseases of ferrets listed below are by body system, or where this is not appropriate in an “Other” category displayed after the body system sections. Those diseases listed below are not exhaustive but rather highlight common diseases encountered with laboratory ferrets.

Nervous System

Canine Distemper
This morbillivirus is essentially 100% fatal in ferrets and disease progression can range from 12 to 42 days. This disease is immunosuppressive and animals die from neurologic dysfunction. Treatment is not recommended. There is one approved distemper vaccine in the US (Fervac-D) which is commercially produced. The presence of suppurative bronchopneumonia in young ferrets is suggestive of this disease.

Gross lesions will be similar to those found in canines. Animals will suffer photophobia (excessive sensitivity to light). Gross lesions will include oculonasal discharge, hyperkaratosis of the planum nasale and footpads, papular rashs around chin and bronchopneumonia. Microscopic lesions will include brightly eosinophilic intracytoplasmic and intranuclear inclusions often in epithelial cells, neurons, WBCs and megakaryocytes. (Studies have shown that the biliary epithelium, urinary bladder and renal pelvis are the most productive places to look for these inclusions. A non-suppurative encephalitis with de-mylination may also be seen.

Rabies
Although the incidence of rabies in ferrets is low, rabies still represents a risk for ferrets, often causing hind limb paralysis. In the US there is currently a commercially available rabies vaccine (Imrab).

There are no gross lesions associated with rabies. Microscopic lesions will include intracytoplasmic eosinophilic viral inclusions, called Negri bodies. These can be demonstrated on HE stains or via standard fluorescent antibody tests.

Neural Tube Defects
NTDs are the most common birth defect in ferrets ranging from cranioschisis (external opening of the skull) to spina bifida. Many variations in defects can be seen.

Gross lesions can include agenesis of the skin and musculature overlaying various areas of the skull and/or the spinal cord. There is also often a degree of nerual tissue loss associated with these lesions. Microscopic lesions can include fusion or deformation of the vertebrae.

Digestive System

General GI

Dental Disease
Broken teeth are common in older ferrets, particularly the upper canines. If the tooth pulp is exposed, extraction or root canal procedures are required. Accumulation of dental calculi is also common in older animals. Tooth root abscesses are common in ferrets as well as dental malformations including supernumerary teeth.

Gross lesions will include discolouration of broken teeth which suggests devitalisation.

Megaoesophagus
The cause of megaoesophagus in ferrets is currently unknown, although its clinical presentation is similar to that found in dogs and cats. In some cases a secondary infection with Candida sp. may been seen. This condition most commonly occurs in middle aged ferrets and any treatment is usually ineffective.

Gross lesions will include a marked dilation of the intrathoracic oesophagus together will ulcerations anywhere along it's length. Concurrent bronchopneumonia may also be present due to aspiration. Microscopic lesions are often inconclusive but can include muscle atrophy, hyperkeratosis of the epithelial lining and yeast within the mucosa resulting in a lymphocytic and neutrophilic inflammatory response.

Gastric Ulcers
Ferrets are very susceptible to stress-related gastric ulcers. These are often associated with Helicobacter mustelae infections, see bacterial GI section below. Large ulcers may result in sudden death due to erosion of sub-mucosal blood vessels.

There are two distinct types of gastric ulcer in ferrets. The most common is associated with the presence of digested blood in the lumen of the stomach. All types of ulcers will be pin point and difficult to see with the naked eye. They will be in highest numbers in the pylorus. Microscopic ulcer lesions will appear as full thickness areas of glandular necrosis and loss which are well demarcated from the surrounding tissue. Bleeding ulcers will be coated with a layer of brown haemoglobin pigment.

Inflammatory Bowel Disease
IBD is very common in middle to old age ferrets and generally falls into two categories; a lymphocytic/plasmacytic form and an eosinophilic form (also known as eosinophilic gastroenteritis). The causes of IBD are multifactorial and the nature of the disease is an uncontrolled inflammatory reaction in the intestine. Strong evidence exists that infections by helicobacter mustelae and ferret coronavirus may eventually result in this condition.

Gross lesions are not normally associated with IBD, aside from generally inflammed GI tract lining. Microscopic lesions will include small to moderate numbers of lymphocytes, plasma cells and eosinophils, mainly within the small intestine. Lymphocytic forms of IBD are associated with intramucosal lymphocytes and villi atrophy, blunting and fusion. Microscopic lesions associated with the eosinophilic form include eosinophilic infiltrates within the small intestine. Additionally, prominent eosinophilic infiltrates may be seen in the mesenteric lymph nodes, liver, pancreas or other abdominal organs.

GI Foreign Bodies
Foreign bodies are commonly seen in young or bored, cage-bound ferrets. They will commonly ingest latex, plastic, foam rubber, towels or other forms of bedding. Anorexia and passage of abnormal stools are common clinical signs.

Gross lesions will include a focal area of abdominal distention with or without haemorrhage. The wall of the intestines at the site of blockage may be thinner than that of the adjacent intestine due to continuous peristaltic movements at the site of blockage. In rare cases, intestinal perforation may be seen. Microscopic lesions may include ulceration, necrosis and thinning of the muscular layers at the site of blockage. In longstanding blockages there will be marked attenuation of villi and granulation tissue.

Neoplasia
The most common form of GI tract neoplasia is lymphosarcoma. The lymphoblastic form of lymphosarcoma is the most common for in the intestine.

Bacterial Infections

Helicobacter mustelae
This bacterial infection can cause disease in significant numbers of ferrets over the age of four via two gastri mechanisms. It can cause stimulation of the lymphoplasmacytic inflammatory response resulting in a loss of granular epithelium, mainly in the pylorus. Secondly this infection has the ability to increase the pH of the stomach. Helicobacter can also be found in the stomach and duodenum of almost all ferrets after weaning. If there are sufficient numbers, this infection can induce chronic, persistant gastritis, ulcer formation and in extreme circumstances gastric lymphoma can occur. Animals over three years of age will rarely show clinical symptoms with a Helicobacter infections.

There are often no gross lesions associated with uncomplicated cases of Helicobacter. Advanced cases may include gastric ulcers and where these occur the gastric mucosa is often lined by moderate amounts of digested blood. Microscopic lesions will include the presence of bacteria in the superficial mucus and in extracellular locations within the gastric glands. The pyloric stomach is the preferred biopsy site.

Proliferative Colitis
Proliferative colitis is uncommon in ferrets but is usually seen in male ferrets under the age of one. This disease can be sporadic and may be present in only one or two animals within a large colony. Clinical signs can include tenesmus and production of small, frequent bowel movements that will contain blood and mucus. Proliferative colitis is caused by a campylobacter-type organism resulting in asymmetrical proliferation of immature epithelium and thickening of the gut wall. This disease is also associated with stress and if untreated can be fatal.

Gross lesions will include noticeable thickening of the colonic wall which will be opaque, rather than being able to see fecal matter through the wall. The mucosa will be prominently "cobblestoned". Microscopic lesions will include a mucosa that is thickened by up to five times via a proliferation of immature epithelial cells with vesicular nuclei and basophilic cytoplasm. There will also be a marked decrease in goblet cells.

Lawsonia intracellularis
Is a major cause of proliferative bowel disease, especially in younger ferrets.

Clostridium perfringens
Clostridium perfringens type A has been reported in black-footed ferret kids.

Gross lesions will include gastric bloat and multifocal intestinal haemorrhage. Microscopic lesions will include marked coagulative necrosis of the intestinal mucosa with numerous adherent bacilli.

Mycobacterium avium
This is a rare infection in ferrets but is most commonly seen in the GI tract and mesenteric lymph nodes. Having said that, macrophages containing the infectious organism have been shown to be able to accumulate in any organ.

Gross lesions are mainly related with mesenteric lymphadenopathy. Microscopic lesions can include the presence of large foamy macrophages with a grayish granular cytoplasm and acid-fast stains may reveal numerous bacilli within these macrophages.

Viral Infections

Epizootic Catarrhal Enteritis
ECE is a coronavirus found in ferrets that can cause epizootics of high morbidity (up to 100%), but low mortality. This infection usually results in diarrhoea that is rapidly dehydrating and can cause mortality in older animals, especially with a concurrent illness. Clinical symptoms will include vomiting and dark green stools with abundant mucus.

There are generally no associated gross lesions although the intestine may be flaccid and contain watery ingesta. For examination of microscopic lesions, tissue samples should be taken from 3-4 different areas of the jejunum as well as other areas of the GI tract. Lesions will include vacuolar degeneration and necrosis of apical enterocytes with marked villi atrophy, fusion and blunting. In severe cases, there is a marked lymphocytic enteritis with large numbers of lymphocytes among mucosal epithelial cells.

Intestinal Parasites

Intestinal parasites are uncommon in ferrets with the exception of coccidia. Toxocara cati, Toxacaris leonina, Ancylostoma sp., Dipylidium caninum and Giardia sp. have all been reported in ferrets. Coccidial species reported in ferrets include Eimeria furo, Eimeria ictidea and Isospora laidlawii. Most coccidial infections will be sub-clinical. Lethal coccidial infections are mainly seen in young kids, although this is rare.

Gross lesions are generally not visible but may include the presence of digested blood in the GI tract of kids with severe infections. Microscopic lesions will include numbers of parasites ranging from low to extremely high depending on the severity of the infection. All stages of the parasite including micro and macrogamemetocytes can be seen. Coccidial infections have also been reportedly found in the hepatobiliary system.