Genetic welfare problems of companion animals

 

Copper Storage Hepatopathy

 

Breed: Bedlington Terrier

 

Condition:  Copper Storage Hepatopathy

Related terms: Bedlington terrier hepatitis; copper storage hepatitis; copper hepatotoxicosis; copper toxicosis;  copper storage liver disease; copper-associated hepatitis; copper-associated hepatopathy; copper-associated liver disease; familial chronic hepatitis.

Outline: Copper storage hepatopathy in Bedlington terriers is caused by a mutant gene that prevents normal copper excretion in the liver. As a result, toxic levels of copper accumulate in this organ leading, after years, to liver failure. The resulting disease, which causes severe malaise, can be acute, leading to death within days, or chronic (persistent and long lasting). Surveys during the 1980s and 90s indicated that 30 to 60% of Bedlington terriers were affected by this disease. There has been success in reducing the prevalence in the Netherlands by avoiding breeding from dogs carrying the mutant gene. A genetic test to identify those with the gene is available.

 


 

Summary of Information

(for more information click on the links below)

 

 

1.           Brief description

Copper storage hepatopathy (liver disease) in Bedlington terriers is an inherited disease in which abnormally high amounts of copper accumulate within the tissues of the liver leading to cell damage and chronic inflammation (hepatitis). Ultimately this results in liver failure due to scarring (cirrhosis) of the liver and to death.

Three forms of the disease occur: (i) asymptomatic – in which signs are yet to develop, (ii) acute -seen in dogs up to six years of age, with the sudden onset of severe illness shown as depression, anorexia (not eating) vomiting and possibly jaundice (yellowing of mucous membranes, whites of eyes and skin), and (iii) chronic – seen in middle-aged dogs with signs of chronic liver damage and sometimes failure which may show vomiting, weight loss, jaundice and abdominal swelling.

The outlook for acutely ill dogs, even with treatment, is poor. There is a better prognosis for chronically ill animals if they are treated early enough.

 

 

2.           Intensity of welfare impact             

The intensity of the welfare impact of the disease is very variable, ranging from mild in the early stages of disease to a severe reduction in the quality of life in the later stages, mainly due to animals feeling unwell. In acute cases affected dogs feel extremely ill, with possible nausea and weakness for the days of their illness. Chronically ill animals may have their quality of life reduced by feeling ill for a period of months to years until death occurs.

Diagnostic tests and treatments for copper storage hepatopathy can also have significant welfare implications.

 

3.           Duration of welfare impact

 

The duration of the effects depend on the form of the disease. In the acute form, welfare is severely compromised and affected animals may die within days; in the chronic form the welfare impact is less intense but is likely to be of long duration: lasting months or years from when copper has accumulated in the liver at a level sufficient to cause damage (commonly by two to four years of age) until death, usually within a few years unless treated successfully (Brewer 1998). Treatment is life-long.

 

4.           Number of animals affected

 

Studies conducted in the 1980’s and 1990’s, indicated prevalences of copper storage hepatopathy from 33% (in the UK) to up to 66% (in the USA) in Bedlington terrier populations worldwide (Herrtage et al 1987, Sevelius & Jönsson 1996). There are few data on the proportion affected currently but, in the Netherlands, the prevalence of the disease in the breed has been reduced from 46% to 11% over 20 years through the introduction of good selective breeding practices (Ubbink et al 2000).

 

5.           Diagnosis

Diagnosis is made using a combination of tests including a full veterinary examination, blood and urine tests, liver ultrasound and a liver biopsy. These tests also help to identify the stage and severity of the condition. 

 

6.           Genetics

 

Copper storage hepatopathy in Bedlington terriers is an inherited autosomal recessive trait caused by a mutation in the COMMD1 gene, in which a large section of the gene has been deleted. Affected individuals have a pair of mutated genes (one from each parent). Carrier individuals have one mutated gene, and although unaffected themselves can pass on the disease to their offspring.

 

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

Carrier and affected animals can now be identified using a genetic test for the mutated gene that is available from the Animal Health Trust (http://www.aht.org.uk/genetics_toxicosis.html).

 

8.          Methods and prospects for elimination of the problem

 

Genetic screening and removal of affected and carrier animals from breeding programmes should decrease, and possibly eliminate, this condition. The development of methods for breeders to maintain the genetic diversity within the breed, whilst not breeding from carriers of this disease, is important to avoid the increase of other undesirable genetic conditions.

 

 


 

For further details about this condition, please click on the following:

 

 

 

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1.           Clinical and pathological effects

 

Copper storage hepatopathy (liver disease) in Bedlington terriers is an inherited disease in which abnormally high amounts of copper accumulate within the tissues of the liver leading to cell damage and chronic inflammation (hepatitis). Ultimately this results in liver failure due to loss of function and scarring (cirrhosis) and to the death of the affected individual.

The liver has many important functions including metabolism of macro and micronutrients, detoxifying substances in the blood, producing bile which runs into the gastrointestinal tract, and producing blood proteins including those involved in clotting. The liver is also the major site for the control of body copper levels.

Copper is a mineral micronutrient that the body needs in very small amounts. It is used as a co-factor in many enzymes eg superoxide dismutase 1, cytochrome oxidase C, and ceruloplasmin. These enzymes are throughout the body, with functions including altering neuropeptides (chemicals in the nervous system including the brain), producing cellular energy, detoxifying oxygen-derived radicals, mobilizing iron, helping coagulate blood and producing normal connective tissue (Rutgers & Rishniw 2005).

Copper is absorbed by the gut, passes into the hepatic portal vein and is transported directly to the liver. Hepatic acinar cells in the liver take up most of the copper. They regulate the amounts in the body either by attaching it to molecules that can transport it around the body and releasing it back into the blood stream or by excreting any excess via the bile duct into the gut.

Specialised organelles of the hepatic acinar cells, the secretory lysosomes, are involved in this excretory process. Lysosomes are membrane-bound cell organelles which function to rid the cell of various waste products and toxins, including copper. Lysosomes release their contents outside the cell into the biliary ducts (a network of tubes which ultimately connect to the gall bladder and the gut at the duodenum). The gene COMMD1 (previously known as MURR1) is involved in controlling this excretory lysosomal pathway (Rutgers & Rishniw 2005).

There are three possible causes of the accumulation of excessive amounts of copper in the body: excessive absorption of copper in the gut, dysfunction of copper metabolism, or dysfunction of its excretion. The form that occurs in Bedlington terriers is impaired copper excretion. This leads to a damaging build up of copper in the liver cells (Ludwig et al 1980).

Excessive levels of copper leads to oxidative stress within the liver cells due to an increased concentration of free radicals, very reactive molecules produced as a by-product of metabolism and which cause cellular damage, and if unregulated, induce chronic hepatitis (Center 1996, Spee et al 2006).

The liver is large organ and can continue to perform its functions even when significantly damaged; however, over time, the damage and scarring increases and it can no longer function adequately. The clinical signs of copper storage hepatopathy in Bedlington terriers are due to the liver damage and its consequent failure. The clinical signs can vary widely and usually fit into one of three forms (Johnson 1995, Sevelius & Jönsson 1996):

Asymptomatic form:

This occurs in the early stages of the disease, before any obvious signs are shown. Changes can be detected by blood tests or liver biopsy. Animals that will become affected can also be detected by a genetic test: that identifies those individuals that have two copies of the abnormal COMMD1 gene.

Acute form:

Bedlington terriers with this form are usually less than six years of age and have rapidly developing liver failure, without a previous history of liver disease. This is caused by sudden liver necrosis (cell death) (Johnson 1995, Sevelius & Jönsson 1996). It is an immediately life-threatening form of the disease, with many dogs dying within 48 to 72 hours of signs first appearing despite intensive treatment (Johnson 1995). Such signs include: depression, anorexia (not eating), lethargy and vomiting. Some affected individuals show marked jaundice (yellowing of mucous membranes and skin) due to rapid onset haemolytic anaemia – this is anaemia (lack of red blood cells) caused by the rupture of the cells due, in this case, to the sudden release of copper into the blood stream (Johnson 1995, Sevelius & Jönsson 1996, Rutgers & Rishniw 2005). Some dogs survive and may have milder, recurrent bouts (Johnson 1995). This acute form of the disease is often preceded by a stressful event such as kennelling, whelping etc (Johnson 1995).

Chronic form:

This form appears with a longer, more insidious course usually in middle-aged dogs. Signs include: depression, weight loss, vomiting, deterioration of general condition, polydipsia (increased frequency of drinking) and polyuria (increasing frequency of urination) with or without jaundice (in this case due to liver failure) and ascites (fluid build-up in the abdomen, giving the affected animal a swollen-bellied appearance) (Johnson 1995, Sevelius & Jönsson 1996, Rutgers & Rishniw 2005).

The prognosis (outlook) for this form of the disease depends on the extent of permanent liver scarring, fibrosis and cirrhosis, but is generally fair with treatment (Sevelius & Jönsson 1996). If the liver is so scarred that little normal functioning tissue remains, the outlook is very poor.

Treatment of copper storage hepatopathy consists of the administration of drugs to decrease the absorption of copper, and other drugs to bind it and increase its excretion, antioxidants to counter the effects of excessive copper and diets that are low in copper. Other treatments that support the damaged or failing liver may also be used (Rutgers & Rishniw 2005). Ideally, treatment, particularly the use of low-copper diets, need to be instigated in asymptomatic dogs prior to liver damage. Early identification of animals homozygous for the recessive gene is therefore vital and is now possible (see later).

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2.               Intensity of welfare impact

The welfare problems caused by copper storage hepatopathy in Bedlington terriers are very variable, ranging from mild in the early stages of the disease to severe in the later stages. In acute cases, affected dogs feel extremely ill, with possible nausea and weakness for the days of their illness. Chronically ill animals may have their quality of life reduced by feeling ill for a period of months to years until their death. Copper storage hepatopathy significantly reduces life expectancy in untreated, and some treated, individuals.

Some of the treatments and diagnostic tests can have welfare implications eg the drug, D-Penicillamine may cause vomiting or anorexia as side effects. Treatment of acutely ill dogs and diagnostic tests for dogs at any stage may involve invasive techniques, hospitalisation and trips to and from the veterinary practice which may cause distress to some dogs.

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3.           Duration of welfare impact

 

In Bedlington terriers this disease leads to liver damage starting by two to four years of age. It progresses to cirrhosis and ultimately death within a few years unless successfully treated (Brewer 1998). Treatment of affected individuals is life-long.

Animals may die of the acute form of the disease within days of signs appearing. In the chronic disease, the animals may be ill for months before dying. With treatment, if the disease is caught early, signs may be minimised. If, however, the animal is already in liver failure it may be impossible to treat all aspects of the disease.



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4.           Number of animals affected

 

Studies conducted in the 1980’s and 1990’s, indicated prevalences of copper storage hepatopathy from 33% (in the UK) to up to 66% (in the USA) in Bedlington terrier populations worldwide (Herrtage et al 1987, Sevelius & Jönsson 1996). There are few data on the proportion affected currently but, in the Netherlands, the prevalence of the disease in the breed has been reduced from 46% to 11% over 20 years through the introduction of good selective breeding practices (Ubbink et al 2000).


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5.           Diagnosis

 

Because of the high prevalence of copper storage hepatopathy in this breed, any Bedlington terrier with suggestive signs may be suspected of having the condition. However, similar signs can occur in other conditions and confirmation depends on a full examination with blood and urine tests, often with additional x-rays and ultrasound of the liver. These tests also help determine the stage of the disease and amount of liver damage/failure that has occurred. Definitive diagnosis is made by biopsy of the liver and examination of the tissue under the microscope using specific staining techniques to reveal copper accumulation.

Genetic testing can now be used to determine an individual’s predisposition to the disease prior to signs or to help in confirming diagnosis.

 

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6.           Genetics

It has been known for a number of years that copper storage hepatopathy in Bedlington terriers is an autosomal recessive condition. Affected dogs have a pair of the mutated genes (one from each parent). Although dogs which carry only one mutated gene, do not develop the disease themselves, they can pass it on to their offspring.

Until recently, although the identity of the mutated gene was known (and labelled COMMD1, [previously known as MURR1]), a specific, reliable genetic test for the mutated gene did not exist. Instead a less reliable DNA satellite marker was used (called C04107) to identify dogs likely to have the mutated gene. This DNA marker had been shown to be linked to the occurrence of the disease, however, this test was not infallible and interpretation of the test was not straightforward.

Now, a test for the mutant COMMD1 gene has been developed. In the mutant gene a large area of DNA has been deleted from the COMMD1 gene (Forman et al 2005). The genetic test is available from the Animal Health Trust in the UK (http://www.aht.org.uk/genetics_toxicosis.html). Other older testing protocols are still available from other laboratories and the reader is recommended to refer to their particulars on interpretation of the tests offered (eg Vetgen - http://www.vetgen.com/canine-ct-marker.html).

 

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

The mutant gene can be carried and passed on by dogs that do not develop the disease themselves, so it is important that all Bedlington terriers are tested prior to mating and only those free of the mutant recessive gene should be used for breeding. Puppies could be tested prior to purchase to check their genetic status if their parents do not have certificates to state they are free of the condition.


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8.          Methods and prospects for elimination of the problem

Research in the Netherlands has shown that the prevalence of copper storage hepatopathy in Bedlington terriers can be significantly reduced by careful identification of affected and carrier individuals and removal of them from breeding programmes, whilst maintaining the “already limited genetic heterogeneity (genetic variation) of the population” (Ubbink et al 2000). This reduction was achieved by screening at least 90% of the population for disease (using less reliable methods than now available). The researchers suggest that with more reliable identification of carriers (now available) eradication of the disease within this breed should be possible (Ubbink et al 2000); however, as they point out, it is highly important to maintain as much genetic diversity within the breed as possible to avoid increased risk of other genetic diseases. This is difficult because of the prevalence of the mutated gene in Bedlington terrier populations. The development of clear methods to maintain genetic diversity is needed.

In the Netherlands, genetic diversity was maintained during the efforts to eradicate copper storage hepatopathy by analysis of every dog’s pedigree and through breeding strategies designed to minimise inbreeding (Ubbink et al 2000). This progress in eliminating copper storage hepatopathy in Bedlington terriers in the Netherlands needed significant cooperation from all breeders, the breed society and the kennel club for the Netherlands and is an example of how other conditions could be addressed.

 

 

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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

Brewer GJ (1998) Wilson disease and canine copper toxicosis. American Journal of Clinical Nutrition 67: 1087S-1090S

Center SA (1996) Chronic hepatitis, cirrhosis, breed-specific hepatopathies, copper storage hepatopathy, suppurative hepatitis, granulomatous hepatitis and idiopathic hepatic fibrosis.  In Strombeck’s Small Animal Gastroenterology (3rd ed.) pp705-765 WB Saunders: Philadelphia, USA

Forman OP, Boursnell ME, Dunmore BJ, Stendall N, van den Sluis B, Fretwell N, Jones C, Wijmenga C, Rothuizen J, van Oost BA, Holmes NG, Binns MM and Jones P (2005) Characterization of the COMMD1 (MURR1) mutation causing copper toxicosis in Bedlington terriers. Animal Genetics 36: 497-501

Herrtage ME, Seymour CA, White RAS, Small GM and Wight DGD (1987) Inherited copper toxicosis in the Bedlington terrier the prevalence in asymptomatic dogs. Journal of Small Animal Practice 28: 1141-1151

 

Johnson SE (1995) Diseases of the Liver in Ettinger SJ and Feldman EC’s (Eds) Textbook of Veterinary Internal Medicine 4th Ed. pp 1313-1358 WB Saunders: Philadelphia, USA

Ludwig J, Owen CA Jr, Barham SS, McCall JT and Hardy RM (1980) The liver in the inherited copper disease of Bedlington terriers. Laboratory Investigations 43: 82-7

Rutgers C and Rishniw M (2005) Copper Storage Hepatopathy. VIN Associate. http://www.vin.com/Members/Associate/Associate.plx?DiseaseId=120. Accessed 11.4.11

 

Sevelius E and Jönsson L (1996) Liver Disease in Thomas DA, Simpson JW and Hall EJ (eds) Manual of Canine & Feline Gastroenterology. pp 191-220. BSAVA: Cheltenham, UK

Spee B, Arends B, van den Ingh T, Penning LC and Rothuizen J (2006) Copper Metabolism and Oxidative Stress in Chronic Inflammatory and Cholestatic Liver Diseases in Dogs. Journal of Veterinary Internal Medicine 20: 1085–1092

Ubbink GJ, Van den Ingh TS, Yuzbasiyan-Gurkan V, Teske E, Van de Broek J and Rothuizen J (2000) Population dynamics of inherited copper toxicosis in Dutch Bedlington terriers (1977-1997). Journal of Veterinary Internal Medicine 14: 172-6

http://www.aht.org.uk/genetics_toxicosis.html

http://www.vetgen.com/canine-ct-marker.html

 

 

 

 

© UFAW 2012

 

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