Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

Miniature Schnauzer 

Miniature Schnauzer

Hyperadrenocorticism

Related terms: Cushing’s disease, canine Cushing’s syndrome

Outline: Hyperadrenocorticism is the disease caused by excessive production of glucocortocoid hormones, almost always as a result of cancer of the pituitary or of one of the adrenal glands. These hormones play key roles in regulating many biochemical processes in the body and many normal functions are affected in this disease. The effects include increased thirst and frequency of urination, increased appetite, abdominal distension, loss of muscle mass and strength, lethargy, loss of fur, and thinning and calcification of the skin. Without treatment affected dogs eventually die due to secondary complications such as diabetes, the formation of blood clots in the circulation and infections that occur due to suppression of the immune system. These cause chronic malaise and discomfort and depending on which parts of the body become affected there can be prolonged pain.

 


Summary of Information

(for more information click on the links below)

1. Brief description

In hyperadrenocorticism (HAC) there is a chronic excess of glucocorticoid hormones, particularly cortisol. Glucocorticoid hormones have multiple effects throughout the body, with roles in the metabolism of carbohydrates, proteins and fats and in reducing inflammation and control of immune responses.

Spontaneous hyperadrenocorticism can be caused either as a result of cancer of the pituitary gland, causing malfunction of its control of the glucocorticoid hormones or as a result of primary disease of the adrenal glands which produce these hormones.  Pituitary cancers are the cause in about 85% of dogs with HAC (Nothelfer & Weinhold 1992, Ramsey & Neiger 2009). The other 15% are caused by primary disease in the adrenal glands. In both types, a benign or a malignant tumour in either one of these glands causes the excessive secretion of glucocorticoids (Ramsey & Neiger 2009). In a few cases there is primary disease in both sites (Nothelfer & Weinhold 1992).

Signs of HAC include: increased thirst and frequency of urination, increased appetite, abdominal distension, loss of muscle mass and strength, lethargy, loss of fur, and thinning and calcification of the skin (Ling et al 1979, Feldman & Nelson 1987). Without treatment affected dogs eventually die due to secondary complications caused by the disease such as diabetes, thromboemboli (blood clots in the blood circulation) and infections that occur due to suppression of the immune system (Ling et al 1979, Hall et al 2003).

2. Intensity of welfare impact   

In the early stages of HAC, the disease and welfare effects are minor but these gradually progress and become increasingly severe if the animal does not receive appropriate and successful treatment. The muscle weakness experienced by animals affected with the disease reduces their ability to exercise and behave normally and dogs with more advanced stages of the disease will tend to feel ill, and the infections and thromboemboli that commonly occur as a result of the disease cause discomfort and pain.

Investigation and treatment of HAC usually requires multiple visits to a veterinary practice, collection of blood samples and undertaking other diagnostic procedures, and hospitalisation, all of which can be stressful. Treatment of the disease usually requires life-long medication with drugs which are potentially dangerous and the effects of which require long-term monitoring (involving ongoing veterinary visits and blood sampling) to ensure efficacy and safety (den Hertog et al 1999, Hall et al 2003, Ramsay 2011a, 2011b).

3. Duration of welfare impact

As the onset of hyperadrenocorticism causes few signs that are readily apparent, the dog may suffer welfare effects for months or years prior to veterinary attention being sought. The welfare issues related to the diagnosis of HAC frequently last a few weeks as confirming the diagnosis is often challenging. Welfare issues related to treatment then last on average for around two years – the average life expectancy of dogs being medically treated for HAC (Barker et al 2005).

4. Number of animals affected

It is believed that Miniature schnauzers have a clear predisposition to this disease (Shell 2007, Wood et al 2007, Stritzel & Distl 2010), but we are unaware of any published data on the proportion of them affected.

5. Diagnosis

The diagnosis of HAC will be suspected by a veterinary surgeon presented with a dog showing the typical signs listed above (see ‘Brief description’). There are also typical changes that can be seen in routine blood and urine tests and sometimes on imaging of the body using x-rays and ultrasound examinations. There are specific tests used to confirm the diagnosis of HAC: the ACTH stimulation test and the low-dose dexamethasone suppression test. Neither of these tests always gives the correct diagnosis, and both may be needed in order to confirm the disease. Other laboratory tests may also be used eg to measure the ratio of cortisol to creatinine in the urine (Hall et al 2003).

6. Genetics

Miniature schnauzers are known to be predisposed to HAC but the genetic basis of the problem is unknown. Some investigations have been made into genes that might be involved but, so far, none have been identified (Van Wijk et al 1997, Hanson et al 2008, De Marco et al 2009).

7. How do you know if an animal is a carrier or likely to become affected?

It is not known whether or not animals may be carriers, ie whether or not some may be able to pass on predisposition to the disease to their offspring without ever developing the disease themselves. Although the genetics of the condition are not known, it seems good advice to avoid breeding from any affected individuals, or from those with any close relatives (parents, siblings, grandparents or the siblings of parents and grandparents) that have been affected by HAC. This is more difficult than with some other genetic diseases because dogs are usually relatively old when diagnosed with HAC.

8. Methods and prospects for elimination of the problem

As far as we are aware, there are currently no organised breeding schemes aimed at tackling the incidence of HAC in the Miniature schnauzer breed. Whilst the genes involved have not been determined, breeding selectively from Miniature schnauzers whose relatives have been free of the disease (and which have good breeding values) is likely to be effective in reducing the number of affected dogs (Indrebo 2006, Bell 2010). Breeding values take account of genetic information and the presence or absence of diseases both in the individual and its relatives. Progress in reducing the prevalence of HAC is likely to be facilitated by greater knowledge of the genetics that underlie the disease.


For further details about this condition, please click on the following:
(these link to items down this page)


1. Clinical and pathological effects

In hyperadrenocorticism (HAC) there is a chronic (long-term) excess of glucocorticoid hormones, particularly of cortisol. Glucocorticoid hormones have multiple effects throughout the body and are involved in metabolism of carbohydrates, proteins and fats, in reducing inflammation and in control of immune responses. They are under a complex control system which is of importance in understanding hyperadrenocorticism.

Positioned at the base of the brain, the pituitary gland, under influence from other parts of the brain, releases a number of hormones. One of these is adrenocorticotrophic hormone (ACTH).  Higher levels of ACTH in the bloodstream stimulate the adrenal glands (which are in the abdominal cavity near the kidneys) to secrete cortisol and other glucocorticoids. These have various effects throughout the body. A high blood cortisol concentration has a negative feedback effect on the brain and pituitary gland that results in reduced secretion of ACTH from the pituitary so that cortisol production rate in the adrenals is decreased (Herrtage 1990).

There are two causes of spontaneous hyperadrenocorticism.

1. In about 85% of cases in dogs, the cause is a tumour of the pituitary gland that causes excessive ACTH production (Nothelfer & Weinhold 1992, Ramsey & Neiger 2009). The cancer cells do not respond to the normal negative feedback control outlined above and so continue to secrete ACTH, no matter how high the blood cortisol concentration. The resulting high levels of ACTH in the blood cause the adrenal glands to produce high levels of glucocorticoids. Over time, the increased activity of the adrenals results in their increasing in size (hypertrophy).

The tumour in the pituitary gland that causes the disease is often less than 1 cm in diameter and is typically benign in behaviour ie it does not cause problems to the gland by growing quickly and destroying the local tissue or by spreading around the body (Herrtage 1990). However, about 10% of these pituitary tumours are larger and cause damage to the brain locally as well as causing hyperadrenocorticism (Feldman & Nelson 1987, Wood et al 2007). 

2.  The other 15% of cases of HAC in dogs are caused by primary disease of the adrenal glands. This may be a benign or a malignant tumour in either of the glands that results in excessive glucocorticoid production, independent of blood ACTH levels (Ramsey & Neiger 2009).

In a few cases, there is primary disease of both pituitary and adrenal glands Nothelfer & Weinhold 1992). Some dogs develop multiple endocrine conditions, for example hyperadrenocorticism along with diabetes mellitus; the commonest breed to be affected with multiple endocrine disease is the Miniature schnauzer (Blois et al 2011).

Hyperadrenocorticism in dogs is most common in middle-age (Feldman & Nelson 1987). The signs appear slowly over months or years and include increased thirst and frequency of urination, increased appetite, abdominal distension, loss of muscle mass and strength, lethargy, loss of fur, and thinning and calcification of the skin (Ling et al 1979, Feldman & Nelson 1987). In a small proportion of cases, in which the cause is a large pituitary tumour, there may also be signs of brain disease (Feldman & Nelson 1987). Without treatment, dogs with HAC eventually die due to one or more of the secondary complications caused by the disease: diabetes, thromboemboli (blood clots) causing blockage of blood flow to vital organs, or infections arising because of suppression of the immune system (Ling et al 1979, Hall et al 2003).

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2. Intensity of welfare impact

In the early stages, the disease and welfare effects of HAC can be minor, but these gradually progress and become increasingly severe unless there is appropriate and successful treatment. The muscle weakness experienced by affected animals reduces their ability to exercise and behave normally and, those with more advanced stages of the disease, tend to feel ill and the infections and thromboemboli that commonly occur cause discomfort and pain.

Investigation of HAC usually requires multiple visits to a veterinary practice, collection of blood samples, other diagnostic procedures, and hospitalisation - all of which can be stressful. Treatment of the disease usually requires life-long medication with drugs that either interfere with cortisol production or which selectively destroy parts of the adrenal glands. These are potentially dangerous drugs, the use of which requires monitoring which necessitates repeated veterinary visits and blood sampling to ensure efficacy and safety (den Hertog et al 1999, Hall et al 2003, Ramsay 2011a, 2011b). Welfare problems related to use of these drugs include over-suppression of, or permanent damage to, adrenal function which causes the dog to feel ill and which may be fatal or, otherwise, requires further permanent drug treatment (Ramsay 2011a, 2011b).

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3. Duration of welfare impact

As the onset of hyperadrenocorticism causes few signs that are readily apparent, affected dogs may suffer some welfare problems for months or years prior to veterinary attention being sought. The welfare issues related to the diagnosis of HAC frequently last a few weeks as confirming the diagnosis is often challenging. Welfare issues related to treatment then last on average for around two years – the average life expectancy of dogs being medically treated for HAC (Barker et al 2005).

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4. Number of animals affected

It is believed that Miniature schnauzers have a clear predisposition to this disease (Shell 2007, Wood et al 2007; Stritzel & Distl 2010), but we are unaware of any published data on the proportion of them affected.

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5. Diagnosis

HAC will be suspected by a veterinary surgeon presented with a dog showing the typical signs listed above (See ‘Clinical and pathological effects’). There are also typical changes that can be seen in routine blood and urine tests and sometimes on imaging of the body using x-rays or ultrasound. There are specific tests that can be used to confirm the diagnosis of HAC. The ACTH stimulation test involves injection of ACTH to stimulate the adrenal glands to produce cortisol. In dogs with HAC, an exaggerated response is expected from the animal’s pathologically enlarged adrenals. In the low-dose dexamethasone suppression test, an injection of an artificial steroid hormone – dexamethasone - is given. In a normal animal, this should be detected in the brain leading to suppression of the production of ACTH by the pituitary gland and thus to a drop in the production of cortisol by the adrenals. However, dogs with HAC do not usually respond in this way. Neither of these tests always gives the correct diagnosis, often both need to be performed. Other laboratory tests may be used sometimes also eg the measurement of the cortisol to creatinine ratio in the urine (Hall et al 2003).

Further tests can be used to determine whether the disease is due to malfunction of the pituitary or an adrenal gland. Measurement of blood ACTH concentration is useful for this, as is ultrasound examination of the adrenal glands to check for the presence and nature of any adrenal tumour. Dogs with the adrenal form of the disease tend to be more difficult to treat and to have a poorer prognosis than dogs with the pituitary form (Hall et al 2003).

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6. Genetics

Miniature schnauzers are known to be predisposed to HAC but the genetic basis of the disease is unknown. Some investigations have been made into genes that may influence the disease in other breeds of dogs but, so far, none of the genes involved have been determined in Miniature schnauzers or other dogs (Van Wijk et al 1997, Hansen et al 2008, De Marco et al 2009).

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7. How do you know if an animal is a carrier or likely to become affected?

The disease can often be detected in affected animals from a young age through examination of the eye and eyelid. The genetics have not been elucidated but the fact that the disease is common in poodles suggests that there is a genetic link and that affected animals are more likely than non-affected animals to have affected offspring. If the eyes and eyelids are found to be normal on examination at two to three years of age then it is unlikely that the dog has this problem or will go onto develop it.

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8. Methods and prospects for elimination of the problem

As far as we are aware, there are currently no organised breeding schemes aimed at tackling the incidence of HAC in the Miniature schnauzer breed. Although the genes involved have not been determined, breeding selectively from Miniature schnauzers whose relatives that have been free of the disease (and which have good breeding values) is likely to be effective in reducing the number of affected dogs (Indrebo 2006, Bell 2010). Breeding values take account of genetic information and the presence or absence of diseases both in the individual and its relatives. Progress in reducing the prevalence of HAC is likely to be facilitated by greater knowledge of the genetics that underlie the disease.

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9. Acknowledgements

UFAW is grateful to Rosie Godfrey BVetMed MRCVS and David Godfrey BVetMed FRCVS for their work in compiling this section.

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10. References

Barker E, Campbell S, Tebb A, Neiger R, Herrtage M, Reid S and Ramsey I (2005) A comparison of the survival times of dogs treated with Mitotane or Trilostane for pituitary-dependent hyperadrenocorticism. Journal of Veterinary Internal Medicine 19: 810–815

Bell JS (2010) Genetic testing and genetic counseling in Pet and Breeding Dogs. 35th World Small Animal Veterinary Association World Congress Proceedings. 2-5th June 2010, Geneva, Switzerland. http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=wsava2010&PID=pr56159&O=VIN accessed 22.7.2011

Blois, SL, Dickie E,Kruth SA and Allen DA (2011) Multiple endocrine diseases in dogs: 35 cases (1996–2009) Journal of the American Veterinary Medical Association 238: 1616-1621

De Marco V, Carvalho LR, Billerbeck AEC and Mendonca BB (2009) Mutation analysis of TPIT in poodle dogs with Cushing's disease. World Small Animal Veterinary Association Congress Proceedings. http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=wsava2009&PID=pr53861&O=VIN accessed 22.7.2011

Feldman EC and Nelson RW (1987) Hyperadrenocorticism. In: Canine and Feline Endocrinology and Reproduction. WB Saunders, Philadelphia pp 137

Hall EJ, Murphy K and Darke P (2003) Hyperadrenocortisim. In: Notes on Canine Internal Medicine. Blackwell Science Limited, Oxford pp 233

Hanson JM, Mol JA, Leegwater PAG., Bilodeau S, Drouin J and Meij BP (2008) Expression and mutation analysis of Tpit in the canine pituitary gland and corticotroph adenomas. Domestic Animal Endocrinology 34: 217-22

Herrtage ME (1990) The adrenal glands. In: Manual of Small Animal Endocrinology editor M Hutchison, British Small Animal Veterinary Association, Cheltenham pp 73

den Hertog E, Braakman JCA, Teske E, Kooistra HS and Rijnberk A (1999) Results of non-selective adrenocorticolysis by O,p'-DDD in 129 dogs with pituitary-dependent hyperadrenocorticism. Veterinary Record 144: 12-17

Indrebo A (2006) Healthy Dog Breeding -The Value of Breeding Programmes. World Small Animal Veterinary Association Proceedings http://www.vin.com/Members/Proceedings/Proceedings.plx?CID=wsava2006&PID=pr15830&O=VIN accessed 22.7.2011

Ling GV, Stabenfeldt GH, Comer KM, Gribble DH and Schechter RD (1979) Canine hyperadrenocorticism: pretreatment clinical and laboratory evaluation of 117 cases. Journal of the American Veterinary Medical Association 174: 1211-5

Nothelfer HB and Weinhold K (1992) Formal pathogenesis, average age and breed distribution in the comparison of 61 Lysodren-treated and 36 untreated cases of canine hyperadrenocorticism which were dissected in the years 1975 to 1991 at the Institute for Veterinary Pathology of the Free University of Berlin. Berliner und Münchener tierärztliche Wochenschrift 105: 305-11

Ramsey I (2011a) Mitotane. In: BSAVA Small Animal Formulary 7th edition, British Small Animal Veterinary Association, Cheltenham UK pp 236

Ramsey I (2011b) Trilostane. In: BSAVA Small Animal Formulary 7th edition. British Small Animal Veterinary Association, Cheltenham UK pp 354

Ramsey I and Neiger R (2009) Canine hyperadrenocorticism. In Bonagura JD and Twedt DC. Eds Kirk’s Current Veterinary Therapy XIV. Saunders Elsevier, St Louis, USA pp 224

Shell LG (2007) Hyperadrenocorticism, Cushings disease Veterinary Information Network Associate http://www.vin.com/Members/Associate/Associate.plx?DiseaseId=1324&FindingList=374872 accessed 8.11.2011

Stritzel S and Distl O (2010) Literaturubersicht uber die Rassedisposition und das familiar gehaufe Auftreten des sekundaren Cushing-Syndroms beim Hund. Kleintierpraxis 55: 117-128

Van Wijk PA, Rijnberk A, Croughs RJ, Meij BP, van Leeuwen IS, Sprang EP and Mol JA (1997) Molecular screening for somatic mutations in corticotrophic adenomas of dogs with pituitary-dependent hyperadrenocorticism. Journal of Endocrinology Investigation 20: 1-7

Wood FD, Pollard RE, Uerling MR and Feldman EC (2007) Diagnostic imaging findings and endocrine test results in dogs with pituitary-dependent hyperadrenocorticism that did or did not have neurologic abnormalities: 157 cases (1989–2005). Journal of the American Veterinary Medical Association 231: 1081-1085

© UFAW 2012


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