Adrenal Diseases in Ferrets in Japan
Yasutsugu MIWA1), Makoto NAKATA1) Asuka KUROSAWA1), Hiroshi SASAI2) and Nobuo SASAKI1)*
1)Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113- 8657 and 2) Kitasuma Animal Hospital, 9-5-8 Yokoo, Suma-ku, Kobe, Hyogo, 654-0131, Japan
(Received 27 May 2008/Accepted 4 August 2008)
ABSTRACT. Adrenal diseases are quite common in Japanese pet ferrets; however, there have been no reports concerning the epidemiology of ferret adrenal disease in Japan. The purpose of this study was to collect epidemiological data on ferret adrenal disease in Japan by sending a questionnaire to veterinarians throughout Japan. Among the 521 cases that met the criteria for this study, 307 were adreno- cortical carcinoma (58.9%), 117 were adrenocortical adenoma (22.5%) and 87 were adrenocortical hyperplasia (16.7%), respectively. Sex, clinical signs, concurrent diseases, age and the sites of the affected adrenal gland in these cases were similar to those reported in North America. Most pet ferrets in Japan are imported from North America, and their husbandry in Japan is similar to that in North America, which may be the cause of the similarity in ferret adrenal disease between North America and Japan. Because a difference in the incidence of ferret adrenal diseases among countries has been reported, further research is necessary to investigate the factors related to the similarities and how to decrease the incidence of adrenal diseases in ferrets in Japan.
KEY WORDS: adrenal disease, ferret, hyperadrenocorticism, Japan.
J. Vet. Med. Sci. 70(12): 1323-1326, 2008
Adrenal diseases are quite common in pet ferrets and have been reported both in Japan and in other countries [1, 2, 5-9, 12]. These diseases are typically seen in middle to older-aged ferrets. The pathophysiology and clinical signs of adrenal diseases in ferrets considerably differ from those of Cushing’s disease in dogs. The plasma cortisol concen- trations of ferrets are rarely increased, while the serum con- centrations of some sex steroid hormones such as 17-alpha- hydroxyprogesterone may be increased due to excessive secretion from the affected adrenal gland(s). The underly- ing cause of this disease is unknown, but several causes have been suggested, including husbandry, genetic factors and premature neutering [7, 11]. Premature neutering has been suggested as a potential cause based on studies in mice [5,7,9]. These studies suggest that gonadectomy at an early age could lead to adrenocoritcal nodular hyperplasia or neo- plasia of adrenal glands and that these affected glands could hypersecrete estrogens or androgens. Additionally, another paper reported that increased levels of sex steroids could be a cause of hyperadrenocorticism in ferrets [10].
Progressive alopecia is the most common clinical mani- festation of the disease in both male and female ferrets. However, seasonal hair loss is often seen in the late winter or early spring in the normal ferret, and the progression of the hair loss resembles that of adrenal diseases. Other com- mon clinical signs include an enlarged vulva in females and dysuria in males. At present, surgery is the best treatment modality because adrenal gland tumors rarely metastasize and removal of the affected gland is curative in most cases [8]. Removal of the left adrenal gland is a simple procedure; however, removal of the right adrenal gland may require a
technically difficult procedure because of its relationship to the vena cava [8]. Therefore, the side of the affected adrenal gland is important for determination of the prognosis of the case.
In our unpublished data on neoplasia in ferrets in Japan, the incidence of adrenal neoplasia was the second highest after insulinoma. These incidences are similar to those reported in epidemiologic research of adrenal diseases in ferrets in North America [5, 7, 14]. However, to the best of our knowledge, a large scale investigation of adrenal dis- eases in the ferret has not yet been reported in Japan.
The purpose of this study was to obtain epidemiologic information on adrenal diseases in the ferret in Japan by sending a questionnaire to veterinarians throughout Japan and to compare the results to the data for North America.
MATERIALS AND METHODS
This study was conducted from January 2000 to Decem- ber 2005. The questionnaire asked about the number of adrenal diseases in the ferret and the following items for each case. In this analysis, only the cases histologically con- firmed to be adrenal diseases were used. The following information, including histopathological diagnosis, clinical signs, sex, age, concurrent diseases and the affected site (right or left) of the adrenal gland (6 items), was obtained. Sex was categorized into male, female, castrated male, spayed female or unknown. Age was categorized into less than 1 month, 1 to 3 months, 3 to 6 months, 6 to 12months, 1 to 2 years, 2 to 3 years, 3 to 4 years, 4 to 5 years, 5 to 6 years, 6 to 7 years, more than 7 years or unknown. Other information, such as treatments, clinical course and out- come of the cases, was obtained as written responses by the responding veterinarians. Information about this study was presented to the members of the Japanese Society of Exotic
* CORRESPONDENCE TO: SASAKI, N., Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
e-mail: miwayasutsugu@hotmail.com
Pet Medicine at the annual conference of the society.
The questionnaire was also placed on the website of this society and was open to all veterinarians. The veterinarians wrote their answers into a Microsoft Excel file and then sent the file to the author by e-mail to facilitate analysis. In addi- tion to this questionnaire, data from two other animal hospi- tals that have treated a large number of ferret cases was added to the analysis.
All answers to the questionnaire were evaluated, and only the cases with the diagnosis confirmed by histological examination of biopsy or necropsy specimens were used in this study.
RESULTS
Completed questionnaires were received from 31 animal hospitals throughout Japan, from Hokkaido to Kyusyu, and 521 cases histopathologically confirmed as adrenal diseases were used for further analysis. The number of ferret cases with adrenal diseases in each animal hospital ranged from 0 to 196.
Among the 521 cases confirmed to be adrenal diseases, 307 were adrenocortical carcinoma (58.9%), 117 were adrenocortical adenoma (22.5%) and 87 were adrenocortical hyperplasia (16.7%), respectively. Other histological diag- noses included anaplastic carcinoma (3 cases), suprarenal medulla tumor (2 cases), leiomyosarcoma (2 cases), hemor- rhage and inflammation (2 cases) and medulla hyperplasia (1 case; Table 1).
Clinical signs were referred in 136 (26.1%) of the 521 cases. The most common clinical sign was alopecia (88 cases, 64.7% of 136 cases) followed by vulva swelling (47% of 77 females) and stranguria (27% of 59 males). Twelve percent of the alopecia cases were accompanied with pruri- tus. Other frequent clinical signs included mammary gland swelling, abdominal distention, lethargy and anorexia (Table 2). Additionally, hypoglycemia was confirmed in 5 cases that showed ptyalism, ataxia and hindlimb paresis, and 4 of the cases had concurrent insulinoma on histology. The patterns of alopecia varied. Among the 88 ferrets with alopecia, 56% had systemic alopecia, 21% had only tail alopecia, 18% had alopecia on the caudal half of the body, 2% had alopecia on the cranial half of the body and 3% had only dorsal area alopecia, respectively. Alopecia only involving the tail, generally recognized to be normal sea- sonal alopecia [9, 12 ,13], was observed in 19 ferrets. His- tology showed that among these 19 ferrets, 11 had adrenocoritical carcinoma (57.9%), 5 had adrenocortical adenoma (26.3%) and 3 had adrenal hyperplasia (15.8%), respectively.
The ferrets with adrenal diseases consisted of 223 cas- trated males, 5 males, 258 spayed females, 13 intact females and 22 ferrets of unknown sex, and the number of females and spayed females was slightly higher (54.3%) than that of males and castrated males. The age at admission was con- firmed in 471 (90.4%) of the 521 cases investigated. None of the cases were diagnosed with the disease before 1 year of
| Histopathologic diagnosis | Incidence | |
|---|---|---|
| Number of cases | % | |
| Adrenocortical carcinoma | 307 | 58.9 |
| Adrenocortical adenoma | 117 | 22.5 |
| Adrenocortical hyperplasia | 87 | 16.7 |
| Anaplastic carcinoma | 3 | 0.6 |
| Suprarenal medulla tumor | 2 | 0.4 |
| Leiomyosarcoma | 2 | 0.4 |
| Hemorrhage and inflammation | 2 | 0.4 |
| Medulla hyperplasia | 1 | 0.2 |
| Clinical signs | Incidence | |
|---|---|---|
| Number of cases | % | |
| Alopecia | 88 | 64.7 |
| Vulva swelling | 36 | 46.8ª) |
| Dysuria | 16 | 27.1b) |
| Mammary swelling | 6 | 4.4 |
| Abodominal distention | 6 | 4.4 |
| Anorexia | 14 | 10.3 |
| Othersc) | 22 | |
a) Percentage based on number of females (n=77).
b) Percentage based on number of males (n=59).
c) PU/PD (4), vomiting (4), diarrhea (2), dyspnea (2), ptyalism (4), ataxia (3), urinary incontinence (1), emaciation (1), hind limb paresis (1).
| Age | Incidence | |
|---|---|---|
| Number of cases | % | |
| Less than 1 year | 0 | 0 |
| 1 to 2 years | 12 | 2.3 |
| 2 to 3 years | 49 | 9.4 |
| 3 to 4 years | 99 | 19.0 |
| 4 to 5 years | 143 | 27.4 |
| 5 to 6 years | 125 | 24.0 |
| 6 to 7 years | 23 | 4.4 |
| More than 7 years | 20 | 3.8 |
| Unknown | 50 | 9.6 |
age. The highest incidence was found in the age range of 4 to 5 years of age (Table 3). In regard to the relationship between age range and type of diseases, 5 carcinomas (41.7%), 5 adenomas (41.7%) and 2 hyperplasias (16.7%) were observed in the ferrets of a younger age group (under 2 years, n=12) and 13 carcinomas (65%), 2 adenomas (10%) and 5 hyperplasias (25%) were observed in the ferrets of an older age group (over 7 years, n=20).
Thirty of the 31 animal hospitals documented concurrent diseases at the time of adrenal disease diagnosis. In these 30 hospitals reported to have 385 ferrets were adrenal diseases. Concurrent diseases were detected in 162 (42.1%) of the 385 cases. The most common concurrent disease found in this study was insulinoma (95 cases: 58.6%). Other concur- rent diseases included prostate disease (12 cases), cardiac disease (10 cases), skin tumor (14 cases) and splenomegaly
| Concurrent diseases | Incidence |
|---|---|
| Number of cases | |
| Insulinoma | 95 |
| Prostate disease (cyst, prostatomegaly) | 12 |
| Skin tumorª) | 14 |
| Liver diseaseb) | 12 |
| Lymphoma | 12 |
| Cardiac disease (hypercardia, murmur) | 10 |
| Splenomegaly | 6 |
| Othersc) | 26 |
a) Intracutaneous cornifying epithelioma, mast cell tumor, mammary gland tumor, apocrine gland cyst, sebaceous gland adenoma.
b) Hemangiosarcoma, cholangioma, hepatic adenoma, hepatic cyst.
c) Chordoma (3), glomerulonephritis (3), chronic nephropathy (2), renal cyst, renal calcification, urolithiasis, cystitis, hemangioma, dermatophytosis, chronic myelocytic leukemia, mammary duct ectasia, stump pyometra, squamous cell carcinoma, duodenum enterocentesis, gastric foreign body, generalized metastasis of adrenal adenocarcinoma, neuroendocrine carcinoma, granuloma, fat necrosis, parathyroid adenoma, urogenital fibroma.
(6 cases; Table 4).
The site of the affected adrenal gland was indicated in 209 of the 521 cases investigated, and the left adrenal gland was affected in 160 ferrets (76.5%), the right adrenal gland was affected in 19 ferrets (9.1%) and the bilateral adrenal glands were affected in 30 ferrets (14.4%), respectively. In 8 of the 30 ferrets with bilateral involvement, both sides were simultaneously affected.
DISCUSSION
In the ferret, adrenal gland diseases are quite common, and their histopathological diagnosis varies [7, 8]. In a pre- vious report, adrenal gland carcinoma was found to be most common [1], while in other reports, the incidence of adreno- cortical hyperplasia and adenoma was higher than that of carcinoma [8, 9, 12]. In the present study, the incidence of adrenocortical carcinoma was highest (58.9%), more than twice that of adrenocortical adenoma (22.5%). The differ- ence in the incidences among the reports is unclear, but the present study indicated adrenal carcinoma is more common in Japanese ferrets.
It has been reported that the incidences of some diseases such as lymphoma and gastrointestinal foreign body are dif- ferent between younger ferrets (younger than 2 years of age) and older ferrets [3, 4, 14]. Similarly the incidences of adre- nal diseases have been reported to be higher in middle-aged to older ferrets (older than 3 years of age) [1, 7-9, 12-14]. In the present study, the age of the affected ferrets ranged from 1 to 7 years old with a peak at 4-5 year of age, and this supports the previous reports.
The number of younger cases with adrenal diseases at 1- 2 years of age was only 12 (2.3%) in the present study. Five of the 12 cases (41.7%) were diagnosed as adrenocortical adenocarcinoma. This result suggests that malignant adre-
nal tumors may occur even in younger ferrets less than 2 years of age.
Various clinical signs were found in the present study. Alopecia was the most common sign (64.7%) followed by vulva swelling in female ferrets and dysuria in male ferrets. These incidences of clinical signs were similar to those in past reports [7, 9, 12-14]. In ferret adrenal diseases, alope- cia is usually symmetric, beginning from the rump and spreading to the cranial part of the body [7, 8, 12]. In the present study, the alopecia pattern seemed to start from the caudal half of the body or tail (39%), although it could start from any part of the body. The highest incidence was gen- eralized alopecia (56%), which could be the result of pro- gression from local alopecia, and this was also similar to previous reports [7-9,12,13]. Previous reports have men- tioned that hair loss involving only the tail could develop seasonally and may not be a pathologic finding [9, 12, 13]. However, in the present study, nearly 60% of the cases with hair loss only involving the tail were diagnosed as adenocar- cinoma by histopathology. It is necessary to clarify the rela- tion between tail alopecia and adrenal diseases in the ferret.
Higher incidences of adrenal diseases have been reported in neutered ferrets than in intact ferrets and in females than in males [8, 12, 13]. The present study also revealed the same tendency. Ferrets in Japan are commonly neutered at an early age (4-6 weeks of age) before being shipped to pet shops as in North America. Several reports have mentioned that premature neutering may play a role in this higher inci- dence of adrenal diseases in neutered ferrets based on stud- ies in mice [5, 7, 9]. On the other hand, one report has suggested that the higher incidence in the female is not a true trend but a presentation bias because female signs are easier to detect than male signs [8]. In the present study, vulva swelling was confirmed in nearly half of the female/ neutered female cases (47%) and dysuria was confirmed in 27% of the male/castrated male cases. These results may support the possibility of a presentation bias.
Previous reports have indicated that insulinoma and sple- nomegaly are the most common concurrent diseases with ferret adrenal diseases [7-9, 12, 13]. In the present study, insulinoma was the most common concurrent disease (58.6%) but splenomegaly was found in only 3.7% of ferrets as a concurrent disease. Splenomegaly is a rather common nonspecific finding in the ferret. Therefore, the veterinari- ans in the present study may not have recorded this finding on the questionnaire. Other concurrent diseases such as prostate diseases and cardiac diseases were similar to those of previous reports [7, 8, 12, 13].
In the present study, the left adrenal gland was more affected than the right, similar to previous reports [1, 9, 12, 13]. The cause of the higher incidence in the left adrenal gland is unknown, but anatomical or physiological reasons might play a role. The right adrenal gland usually adheres to the vena cava, and it is more difficult to detect the lesion at this site. Veterinarians often do not consider the tumors of the right adrenal gland as a surgical indication. Generally, it is not common to biopsy the affected adrenal gland when the
veterinarian decides against surgery. Thus, these cases were excluded from this questionnaire since a definitive diagno- sis was not made. This may have influenced the higher inci- dence of the left adrenal gland in the present study.
As previously described, the results obtained in the present study are similar to those of previous reports in North America. Most pet ferrets in Japan are imported from North America, and their husbandry in Japan including diet is similar to that in North America. Differences in the inci- dences of ferret adrenal diseases among countries have been reported [2, 7, 11, 12]. The genetic similarity of the ferrets in North America and Japan or gonadectomy at an early age may play an important role for the high incidences of adre- nal diseases in the ferrets of these areas. Further research is necessary to clarify the true cause of the disease to decrease the incidence of adrenal diseases in ferrets.
ACKNOWLEDGMENTS. The present research was com- pleted by the united efforts of a great number of cooperating Japanese veterinarians and their staffs. The authors grate- fully acknowledge them for their contributions in taking the time to investigate their medical records. This work was supported in part by the Japanese Society of Exotic Pet Medicine.
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