Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

Labrador Retriever Labrador Retriever

Copper Associated Chronic Hepatitis

Related terms: Copper storage disease, copper toxicosis; Copper Storage Hepatopathy

VeNom term:  Copper-associated chronic hepatitis (VeNom code: 584)

Related conditions: liver failure, liver toxicity, inflammation of the liver, hepatic encephalopathy, cirrhosis

Outline: Copper associated chronic hepatitis is a progressive inflammatory disease of the liver which is caused or worsened by high levels of copper in the liver and bloodstream. The condition affects middle-aged to older dogs, and Labrador retrievers are at higher risk than other breeds of developing the disease. Chronic hepatitis is characterised by inflammation, scarring and destruction of the cells and tissue of the liver, which can result in loss of liver function and, if left untreated, liver failure. It is currently not known why the Labrador is predisposed to develop the condition, but a genetic defect in copper metabolism in this breed is likely. Early diagnosis of chronic hepatitis is difficult because the clinical signs are non-specific and include weight loss, weakness, fatigue, vomiting, diarrhoea and abdominal pain. Signs of later stages of the condition include abdominal swelling and jaundice, and confusion/altered consciousness may occur when increased copper levels affect brain function.


Summary of Information

(for more information click on the links below)

1. Brief description

Copper-associated chronic hepatitis is an inflammatory condition of the liver which is caused or worsened by excess copper accumulation in the liver and bloodstream. The tissues of the liver become damaged when high levels of copper cause oxidative stress and cell damage. The liver becomes inflamed and its tissues are destroyed and replaced with scar tissue, which reduces the normal function of the liver; which include protein synthesis, detoxification of metabolites and the production of bio-chemicals required for digestion. The damage caused by chronic hepatitis is progressive, and over time the liver stops functioning normally and, if not treated successfully, will result in liver failure and death. In the early stages of chronic hepatitis, dogs will suffer from weight loss, weakness, fatigue, vomiting, diarrhoea and abdominal pain. These signs are vague and non-specific and therefore an early diagnosis of chronic hepatitis is not easy. Treatment is available for early stages of the condition and is focused on reducing and stabilising the levels of copper in the body.

Excess copper in the blood is common in Labradors with chronic hepatitis, and relatives of affected dogs also have a high level of copper in their blood and this suggests the condition is likely to be inherited. However, the exact cause of copper accumulation and chronic hepatitis in the breed is not known, due to a lack of research-based evidence.

2. Intensity of welfare impact   

Dogs with chronic hepatitis are likely to feel unwell with fatigue, weakness and abdominal pain, and they may be affected for months or years before the condition is diagnosed and/or treatment or death occurs. Medical treatment is available for early stages of the condition, although treatment is not always successful in managing the clinical signs and preventing progression of the condition. As the disease becomes more advanced, the prognosis becomes poorer and other signs can develop such as yellowing of the skin (jaundice, due to liver failure), or abdominal swelling due to a fluid build-up in the abdomen (ascites). Confusion or altered consciousness (due to hepatic encephalopathy) may also occur as the excess copper in the blood enters the brain, and may cause damage to the nerves and cells in the brain which are involved in the coordination of movement, processing of stimuli and mood regulation. Death can be caused by liver-related complications, pneumonia, or renal failure.

3. Duration of welfare impact

Chronic hepatitis is usually reported to be diagnosed in middle aged dogs, eg from 7 years of age, but this can range from 2.5 to 16 years. Usually, by the time dogs are diagnosed with this condition, the damage to the liver is enough to cause dysfunction, and therefore the survival time and response to treatment may be poor.

4. Number of animals affected

Labrador retrievers are at higher risk of developing the condition compared with other breeds. Bitches seem to have a greater risk of developing chronic hepatitis than male dogs.

5. Diagnosis

The clinical signs of chronic hepatitis are non-specific and may only be intermittently presented or not at all, so an early diagnosis is difficult. Most animals are presented late in the course of the disease when they show dramatic weight loss and persistent diarrhoea and vomiting.

Measurement of increased blood serum enzymes will indicate the presence of chronic hepatitis but a liver sample is required to confirm a diagnosis.

6. Genetics

Evidence suggests there may be an inherited defect in liver copper metabolism in Labrador retrievers, although the exact nature of the defect or how this is passed to offspring is unknown.

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

Since the genetic defect has not been identified, there is currently no way of knowing which animals are more at risk of developing the condition. We do know that the condition is more prevalent in Labrador retrievers than is expected.

8. Methods and prospects for elimination of the problem

Research is required to identify the exact mechanisms involved in copper-associated chronic hepatitis and the mode of inheritance. In the absence of further information, the best advice that can be offered to prospective breeders is to avoid breeding between affected individuals or from dogs with affected relatives, including grandparents, siblings, previous offspring and siblings of parents.

 

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


1. Clinical and pathological effects

Chronic hepatitis is a term given to a group of inflammatory liver diseases which arise for a variety of different causes, including metabolic, infectious, toxic and autoimmune factors. Chronic hepatitis is the term used regardless of the cause of the disease because the diseases are similar in diagnosis, clinical signs and management, but there is a hereditary form of the disease affecting Labrador retrievers which is likely to be caused by an inherited defect that affects the way the liver metabolises copper. Little is known about the exact causes of chronic hepatitis, its treatment and prognosis, and there is a need for greater research (Watson 2004).

Chronic hepatitis is characterised by destruction of the cells and tissue of the liver, inflammation mediated by immune cells (mononuclear cells such as monocytes and lymphocytes) and regeneration, thickening and scarring (fibrosis) of the connective tissues in the liver. In a healthy liver, liver enzymes, such as alkaline phosphatase (ALP) and alanine aminotransferase (ALT) drive chemical reactions for metabolism, detoxification and other vital functions, and these enzymes are mostly contained within the liver. When the liver becomes damaged, these enzymes leak out into the blood, and tests for ALP and ALT enzymes in the blood can identify liver damage. The liver has a remarkable ability to repair itself and can continue to function even when there is significant cell and tissue damage. Over time, however, the progressive damage and scarring caused by chronic hepatitis means that the liver cannot function adequately and may eventually fail to function at all. Cirrhosis, which is where normal cells are replaced by poor or non- functioning scar tissue, causes an abnormal liver structure which can be identified from samples of the liver. Cirrhosis may occur at the end stage of the condition and this damage is irreversible.

Clinical signs of the early stages of chronic hepatitis vary widely and include anorexia, depression, weakness, fatigue, weight loss, vomiting, diarrhoea, excessive drinking (polydipsia) and excessive urination (polyuria). Some dogs may present with abdominal pain. These signs are vague and non-specific and therefore an early diagnosis of chronic hepatitis is not easy.

The exact cause of copper accumulation and chronic hepatitis in Labrador retrievers is currently unknown due to a lack of research-based evidence. The cause may be similar to that in Bedlington terriers where a hereditary defect inhibits the excretion of copper into bile (Forman et al 2005; see also the bedlington-terrier-copper-storage-hepatopathy condition on this UFAW site), resulting in a harmful accumulation of copper in the cells of the liver (called Wilson’s disease in humans). Copper is an essential micronutrient for all living organisms, since the metal is required for the generation and function of several enzymes, electron transport proteins and antioxidant molecules. Absorption of copper occurs in the stomach and small intestine, and the copper is carried by transporter proteins (metallothionein, ceruloplasmin) to the liver via the hepatic portal vein. Enzymes produced by the liver are responsible for binding copper to these transporter proteins, and also for removing excess copper by secreting it into bile. When these mechanisms are damaged or defective, copper accumulates in the liver because it cannot be transported to the blood, or excreted into bile. Excessive copper concentrations lead to oxidative stress in the liver cells due to an increased concentration of very reactive free radicals, which cause cellular damage. In the inherited form of chronic hepatitis, copper accumulation is localised to the central lobular region (centrilobular) region of the liver, as opposed to other forms of hepatitis (eg viral) which usually affect the outer regions of the tissue. The cells in the centrilobular region of the liver are near to the portal vein, which takes blood from the gastrointestinal tract rich in nutrients to the liver, and are important for glycolysis, lipogenesis and drug detoxification.

There is a wide range for normal hepatic copper levels in dogs, and liver copper concentrations less than 2,000 parts per million on a dry weight basis (ppm dw) appears to have no adverse effect on the dog’s health. In a study of liver copper concentrations of 16 Labrador dogs with chronic hepatitis, all dogs had copper levels greater than this safe level (the range was 2,375 to 4,972 ppm dw; Smedley et al 2009). These dogs also had elevated levels of iron in the liver, which may be a secondary effect of chronic liver inflammation, or it may be directly related to the abnormal copper metabolism, depending on where the defect lies in the copper absorption and excretion pathways. It is possible that the iron and copper react (since they are both oxidants) to contribute to the lesions and inflammation, but this is currently unknown. Copper accumulation in the liver occurs both in Labrador dogs affected with chronic hepatitis and also in related dogs who do not show outward signs of the condition (Hoffmann et al 2006). The storage of copper in its nontoxic form may occur, and exhaustion of cellular systems which protect against oxidative damage by free reactive copper, or an additional stressor that affects protective mechanisms, may be necessary for copper accumulation to cause hepatitis.

There are a range of stages and severity of chronic hepatitis, and this is scored on the extent of scar tissue in the liver (none, mild, moderate, severe or cirrhosis) and on the severity of liver cell death and inflammation (minimal, mild, moderate, severe), respectively (Sterczer et al 2001).

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2. Intensity of welfare impact

Dogs with chronic hepatitis are likely to show signs of malaise and their welfare may be affected for months or years before diagnosis and/or treatment are required or death occurs. In the early stages, dogs may feel unwell, nauseous and weak. As the disease advances, dogs may show extreme discomfort and pain. Medical treatment is available for the early stages of the condition, although treatment is not always successful in managing the clinical signs and preventing disease progression. Treatment is focused on removing the excess copper; termed chelation therapy. A drug, Penicillamine, binds to copper and leads to the excretion of copper in the urine. Once the levels of copper have stabilised, as seen through the results of blood and urine tests, dogs can be given zinc to maintain stable copper levels in the body; zinc stimulates a protein in the cells of the gut which binds copper and prevents its absorption into the blood and transport to the liver. Dogs may be restricted to low-copper diets. Due to various side-effects, such as nausea, vomiting or fever, treatment may not improve the quality of life of the dog in the short-term but may improve the life expectancy.

As the disease becomes more advanced, the prognosis becomes poor and other signs can develop such as yellowing of the skin (jaundice) due to a failure of the liver to remove toxins, or painful or uncomfortable abdominal swelling (ascites) due to a fluid build-up in the abdomen. Confusion or altered consciousness (hepatic encephalopathy) may also occur since the excess copper in the blood enters the brain, and may cause damage to the nerves and cells in the brain which are involved in the coordination of movement, processing of stimuli and mood regulation.

In dogs in which the disease has progressed, death can be caused by liver-related complications, pneumonia, or renal failure. Dogs with enlarged livers are prone to develop difficulties with normal blood clotting due to abnormally low levels of blood thickening agents (thromboplastin) and platelets (thrombocytopenia), and these dogs are considered to be at a higher risk of death.

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3. Duration of welfare impact

Chronic hepatitis is usually reported in middle aged dogs, eg from 7 years of age, when clinical symptoms first become apparent but diagnosis can range from 2.5 to 16 years. Shih et al (2007) report that the average (median) survival time of dogs after diagnosis was 1 year (range: 1 day to 7.2 years). This is likely because the early signs are not well recognised and the condition had progressed.

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4. Number of animals affected

Within a veterinary hospital population, the incidence of chronic hepatitis in Labrador retrievers was 1.2% and this was significantly higher than in other breeds (0.7%; Shih et al 2007). In a Dutch referral database, the Labrador retriever breed had the highest number of cases of chronic hepatitis (16 Labradors compared to the second highest of 4 in American Cocker Spaniels; Poldervaart et al 2009).

In the UK, when comparing the breeds found within a population of dogs with chronic hepatitis against a control group from a microchipping database, Labrador retrievers were found to have increased risk of chronic hepatitis (odds ratio: 2.0, 95% confidence interval: 1.6-2.5; Bexfield et al 2012). Females seem to have a greater risk of developing chronic hepatitis than male dogs (Bexfield et al 2012; Poldervaart et al 2009), suggesting that sex-related hormones may be involved in the cause or the exacerbation of symptoms of the condition.

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5. Diagnosis

Since the clinical signs are non-specific and may only be intermittently presented, an early diagnosis is difficult, and therefore most animals are presented late in the course of the disease, when it has progressed. Furthermore, some dogs may be asymptomatic, ie do not show any outward signs, and these dogs may only be diagnosed following abnormalities shown in routine blood and stool sample tests.

Raised levels of  serum enzymes, such as alkaline phosphatase (ALP) and alanine aminotransferase (ALT), are the best initial screening tool for the presence of chronic hepatitis in Labrador retrievers (Shih et al 2007), since these enzymes are not usually found in high levels in the blood. A liver sample is usually required to confirm diagnosis of chronic hepatitis, taken via a laparoscope. Typical changes which can be seen in the liver tissue include inflammation, fatty deposition, fibrosis or cell death (Smedley et al 2009). It is suggested that a diagnosis of chronic hepatitis should be made after a documented increase in alanine aminotransferase (ALT) levels for a minimum of 4 months, with concomitant histological evidence of the characteristic liver damage described above during this period. Many chronic liver diseases, however, only become apparent in the end stages.

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6. Genetics

Chronic hepatitis is likely to be a complex inherited disorder, involving multiple genes. In one study of Labrador retrievers, evaluation of family members of dogs affected with chronic hepatitis revealed that these family members had raised levels of copper in their liver but at a level that did not cause the disease (subclinical hepatic copper accumulation (Hoffmann et al 2006). This suggests an inherited defect in hepatic copper metabolism, although the exact nature of the defect or mode of inheritance is unknown in this breed.

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

The Labrador retriever breed is significantly at risk of developing the condition but the mode of inheritance of copper-associated chronic hepatitis has not yet been determined for the breed, and therefore there is no way to tell specifically which animals are likely to be affected by the condition.

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8. Methods and prospects for elimination of the problem

Research is required to identify the exact mechanisms involved in copper-associated chronic hepatitis and the mode of inheritance. Affected dogs should not be bred from, but unfortunately the condition is unlikely to show until after breeding age has been reached, and often it only occurs after the dog has been retired from breeding. This makes it particularly important that the genetics of the disease are elucidated and a predictive test developed.

Since hepatitis is likely to involve multiple genes, of which very little is known, the advice that can be given to eliminate the problem is limited (Meyers-Wallen 2003). For such complex inherited disorders, a multi-approach strategy using health screening schemes, pedigree breed information and genome-wide estimated breeding values is recommended to reduce the problem (Farrell et al 2015). With the current state of knowledge on the causal factors of hepatitis, the best advice that can be offered to prospective breeders is to avoid breeding between affected dogs or from dogs with affected relatives, including grandparents, siblings, previous offspring and siblings of parents.

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9. Acknowledgements

UFAW thanks Dr Emma Buckland (BSc, PhD), Dr David Brodbelt (MA VetMB PhD DVA DipECVAA MRCVS) and Dr Dan O’Neill (MVB BSc MSc PhD MRCVS) for their work in compiling this section.

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10. References

Bexfield NH, Buxton RJ, Vicek T, Day MJ, Bailey SM, Haugland SP, Morrison LR, Else RW, Constantino-Casas F and Watson PJ (2012) Breed, age and gender distribution of dogs with chronic hepatitis in the United Kingdom. Veterinary Journal 193: 124–8. doi:10.1016/j.tvjl.2011.11.024

Farrell LL, Schoenebeck JJ, Wiener P, Clements DN and Summers KM (2015). The challenges of pedigree dog health: approaches to combating inherited disease. Canine Genetics and Epidemiology 2: 3. doi:10.1186/s40575-015-0014-9

Forman OP, Boursnell MEG, 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. doi:10.1111/j.1365-2052.2005.01360.x

Hoffmann G, Ingh, TSGAM, Bode P and Rothuizen J (2006). Copper-associated chronic hepatitis in Labrador Retrievers. Journal of Veterinary Internal Medicine 20: 856–861. doi:10.1111/j.1939-1676.2006.tb01798.x

Meyers-Wallen VN (2003) Ethics and genetic selection in purebred dogs. Reproduction in Domestic Animals 38: 73–6

Poldervaart JH, Favier RP, Penning LC, van den Ingh, TSGAM and Rothuizen J (2009) Primary hepatitis in dogs: A retrospective review (2002-2006). Journal of Veterinary Internal Medicine 23: 72–80. doi:10.1111/j.1939-1676.2008.0215.x

Shih JL, Keating JH, Freeman LM and Webster CRL (2007) Chronic hepatitis in Labrador Retrievers: Clinical presentation and prognostic factors. Journal of Veterinary Internal Medicine 21: 33–39. doi:10.1111/j.1939-1676.2007.tb02925.x

Smedley R, Mullaney T and Rumbeiha W (2009). Copper-associated hepatitis in Labrador Retrievers. Veterinary Pathology 46: 484–90. doi:10.1354/vp.08-VP-0197-S-FL

Sterczer A, Gaál T, Perge E and Rothuizen J (2001) Chronic hepatitis in the dog - a review. The Veterinary Quarterly 23: 148–52. doi:10.1080/01652176.2001.9695104

Watson PJ (2004) Chronic hepatitis in dogs: A review of current understanding of the aetiology, progression, and treatment. Veterinary Journal 167: 228–41. doi:10.1016/S1090-0233(03)00118-7

© UFAW 2015


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By Erikeltic at English Wikipedia [CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons