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Genetic Welfare Problems of Companion Animals
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Shar Pei
Amyloidosis
Related terms: generalised amyloidosis; renal amyloidosis
VeNom term: Amyloidosis (VeNom code: 383).
Related conditions: Shar-pei fever; recurrent fever of unknown origin, chronic inflammation; chronic kidney failure
Outline: Amyloidosis is a condition that occurs when amyloid, a substance of abnormally folded proteins, is deposited in various organs of the body. Amyloids cause damage by displacing normal cells. In Shar-peis, there is significant amyloid deposition in the kidney, which leads to decreased function, and failure can occur, which may be fatal. Amyloidosis in Shar-peis is associated with another hereditary disorder - familial Shar-pei fever, which is characterised by intermittent swollen painful hocks, abdominal pain, diarrhoea and anorexia. It is thought that dogs with familial Shar-pei fever are more susceptible to go on to develop amyloidosis, due to the chronic inflammatory process associated with the condition.
The clinical signs of amyloidosis are related to progressive kidney damage, and include excessive drinking and urination, dehydration, poor coat quality, pale or yellow mucous membranes, lethargy, lack of appetite (inappetance) and weight loss. Commonly Shar-peis with the condition develop amyloidosis before 6 years of age, although the progression of the disease in variable. For some affected dogs, the deposition of amyloid may occur slowly, and kidney function may remain adequate for several years. For others, the deposition of amyloid may be rapid and severe, with kidney failure developing within one year.
The condition is thought to be an autosomal recessive inherited trait in Shar-pei dogs, but there is currently no way to genetically determine which animals are likely to be affected. It is therefore recommended that breeding from affected dogs is avoided, and from those with affected relatives, including grandparents, siblings, previous offspring and siblings of parents.
Summary of Information
(for more information click on the links below)
1. Brief description
Amyloidosis involves the extracellular deposition of insoluble, fibrous proteins – amyloids – into various tissues of the body. Amyloids are inappropriately folded versions of normal proteins and polypeptides, which have collected together to form insoluble fibrils. A range of different unrelated proteins can form an amyloid but the most common type is derived from serum amyloid A.
In Shar-pei dogs, amyloids derived from serum amyloid A are primarily deposited in the kidney, and to a lesser extent, in other tissues such as the spleen, stomach, intestines, liver, thyroid and heart. These amyloids are more difficult for the body to break down than normal proteins and so build up and displace normal healthy tissue, disrupting the normal processes of the kidney. Affected kidneys become enlarged, inflamed and unable to function as normal. They are unable to filter the toxic waste products of the body, such as urea, from the blood, and are also unable to reabsorb valuable amino acids and protein back into the body and lose them into the urine. As the disease progresses, there is more damage to the kidney tissue as it is replaced with amyloid filbrils, and eventually this causes failure which can be fatal.
Amyloidosis in Shar-peis is associated with another hereditary disorder - familial Shar-pei fever, which is characterised by intermittent swollen painful hocks, abdominal pain, diarrhoea and anorexia. It is thought that dogs with familial Shar-pei fever are more susceptible to developing amyloidosis, due to the chronic inflammatory process associated with the condition.
Affected dogs may have nonregenerative anaemia, as a result of protein loss from the blood and may show abnormally high levels of nitrogen and phosphate in the blood (azotemia, hyperphosphatemia). This in turn leads to excessive acidity of the blood (metabolic acidosis), which interferes with normal body functions. Without intervention, these toxins may build up in the blood and result in coma and death of the affected animal. The clinical signs of amyloidosis are related to progressive kidney damage, and include dehydration, poor coat quality, pale mucous membranes eg in the mouth, gingivitis (inflammation of the gums) excessive drinking and urination (polydipsia, polyuria), lethargy, inappetance and weight loss.
2. Intensity of welfare impact
The clinical signs of amyloidosis vary in relation to the severity of kidney damage. Dogs with significant amyloid deposition in the kidney will generally feel unwell, as damage starts to take place. They may be lethargic and weak, due to both the loss of protein and the build-up of toxic water product in the blood. Affected dogs have a diminished appetite but with excessive drinking and urination and episodes of vomiting. Some affected dogs will have severe gingivitis (inflamed gums), which is painful, and this will result in further diminished appetite and subsequent weight loss. Underlying inflammatory disease, such as ‘Shar-pei fever’ can cause painful swelling of the hocks and abdomen, as well as diarrhoea and anorexia.
The condition is progressive and untreatable, leading to death by kidney failure as more healthy tissue is replaced with the amyloid substance. Dogs can be given symptomatic treatment of chronic kidney failure. The rate of progression of kidney failure is usually rapid in the late stages of the condition; once an affected cat has developed moderate build-up of waste products in the blood (azotemia and hyperphosphatemia).
3. Duration of welfare impact
Commonly Shar-pei dogs are diagnosed with amyloidosis before 6 years of age, and this is younger than for amyloidosis found in dogs of other breeds. For some affected dogs, the deposition of amyloid may occur slowly, and kidney function may remain adequate for several years. For others, the deposition of amyloid may be rapid and severe, with kidney failure developing within one year.
4. Number of animals affected
Amyloidosis is rarely reported in the scientific literature, and this may indicate the condition is rare or that it is underreported due to a lack of diagnosis of non-specific clinical signs and the sudden death of the animal before the disease is recognised or diagnosed. Shar-pei dogs have a significantly increased risk of developing amyloidosis compared to other breeds or crossbreeds.
5. Diagnosis
A diagnosis can be made by identifying amyloid deposits in kidney biopsy samples. By the time clinical signs are noticeable, and amyloidosis is suspected, there will have been significant amyloid deposition and associated kidney damage, and therefore diagnosis is often made on post-mortem examination.
6. Genetics
Shar-peis have an inherited predisposition for amyloidosis, and an autosomal recessive trait is suspected. A recessively inherited trait means that a dog needs to inherit two copies of the mutated gene, ie one from each parent, for it to be affected by the disease. If a dog only has one copy of the mutation, ie from only one of the parents, the dog will not be affected but will be a carrier, and may pass on the mutated gene to some of their offspring. If two carrier dogs, carrying one copy of the mutated gene each, are mated together, 25% of their offspring are likely to be affected and a further 50% will be carriers of the condition.
7. How do you know if an animal is a carrier or likely to become affected?
Genetic tests for identifying Shar-pei fever or amyloidosis in dogs are currently unavailable. Dogs which show recurrent fever of unknown origin or ‘Shar-pei fever’ are thought to be more susceptible to developing amyloidosis. We know that amyloidosis is more prevalent in Shar-peis, and that the disease occurs within families as a recessive trait, which means that some dogs will carry the genetic mutation without being clinically affected. Therefore the relatives and offspring of affected dog are likely to carry the genetic mutations and may produce affected offspring if mated to an affected dog or another carrier.
8. Methods and prospects for elimination of the problem
Although the mode of inheritance of amyloidosis in Shar-pei dogs has been identified, it is not known whether the associated genetic mutation involves only one mutation or a more complex set of multiple genes. Other factors such as ‘Shar-pei fever’ are involved in the development of amyloidosis. Further genetic testing is required and the development of screening tools to identify dogs that are affected, carriers or unaffected. In the interim, it is recommended that breeding from affected cats is avoided, and from those 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)
- Clinical and pathological effects
- Intensity of welfare impact
- Duration of welfare impact
- Number of animals affected
- Diagnosis
- Genetics
- How do you know if an animal is a carrier or likely to become affected?
- Methods and prospects for elimination of the problem
- Acknowledgements
- References
1. Clinical and pathological effects
Amyloidosis involves the extracellular deposition of insoluble, fibrous proteins – amyloids – into various tissues of the body. Proteins are formed when molecules called amino acids are linked together. During this process, the protein commonly folds into characteristic 3D shapes; the shape being dependent upon the amino acids that go to make it up and essential for their normal function. Amyloids are inappropriately folded versions of normal proteins and polypeptides, which have aggregated together to form insoluble fibrils. A range of different proteins can form an amyloid, but the most common type is derived from serum amyloid A (DiBartola et al 1990, Johnson et al 1995). Serum amyloid A protein is formed mainly in the liver in response to inflammatory diseases and infections when it plays a role in cholesterol transport and as a chemoattractant in the inflammatory processes (Urieli-Shoval et al 2000). Chronic inflammation or overstimulation of the pro-inflammatory results in a sustained abnormally high level of serum amyloid A. In such high concentrations, serum amyloid A split into fragments that have an increased likelihood of clumping together. Because of their rigid and misfolded structure these proteins function poorly and are difficult for the body to break down. They are removed from the cell to the extracellular space where they combine with other insoluble substances, to form amyloids. These amyloids are then deposited into various tissues of the body.
Amyloids are primarily deposited in the kidney, especially in the renal medulla region of the kidney (Segev et al 2012), and to a lesser extent, other tissues such as the stomach, intestines, thyroid and heart (DiBartola et al 1990). The fibrous amyloid substances build up and displace healthy tissue, disrupting the normal processes of the kidneys. The kidney become enlarged, inflamed and unable to function as normal. There is progressive damage as more kidney tissue is replaced with amyloid fibrils, and eventually this causes kidney failure, which can be fatal.
In affected dogs amyloid deposition is commonly found in the medullary interstitial and glomerular regions of the kidney, which are involved in the absorption of water and filtration of the blood. As the kidneys become more damaged, thickening and scarring of tissue (fibrosis) and lesions (necrosis) occur, which promotes further loss of function, towards end-stage renal disease (DiBartola et al 1990). Amyloids were deposited in the glomeruli of the kidneys in 9 of 14 (64%) Shar-pei dogs with amyloidosis (DiBartola et al 1990); this is where filtration of the blood occurs and results in, proteins being lost from the blood and into the urine (proteinuria). Affected dogs may have nonregenerative anaemia, due to the continued loss of protein from the blood. They may also show abnormally high levels of nitrogen and phosphate in the blood (azotemia, hyperphosphatemia) and metabolic acidosis, which is excessive acidity of the blood due to the kidneys reduced ability to excrete waste products, toxins and acid from the blood and which interferes with normal body functions. Jaundice - yellowing of the eyes, skin and mucous membranes - may occur, due to high levels of bilirubin in the blood (hyperbilirubinemia) which is produced by the breakdown of red blood cells due to the altered acidity. Without intervention, these toxins may build up in the blood and cause coma and death.
The clinical signs of amyloidosis relate to the progressive kidney damage caused by the condition, and include dehydration, poor coat quality, gingivitis (inflammation of the gums) excessive drinking and urination (polydipsia, polyuria), lethargy, inappetance and weight loss (DiBartola et al 1990, Segev et al 2012) In addition, characteristic to Shar-peis, there is often a history of intermittent fevers, and/or swelling of the hock (tibiotarsal) joints – between the upper leg and lower leg (DiBartola et al 1990).
Familial Shar-pei fever is a hereditary disorder, occurring in up to 23% of Shar-peis (May et al 1992). It is occurs intermittently, often resolves spontaneously, and is characterised by swollen painful hocks, abdominal pain, diarrhoea and anorexia. In a study of Shar-pei dogs with amyloidosis, 20 of 28 dogs had both recurrent fever of unknown origin and amyloidosis, and often the fever presentation occurred 2 or more years earlier than the diagnosis of amyloidosis (Rivas et al 1993). It is therefore considered that recurrent fever of unknown origin is an early indicator of the genotype responsible for amyloidosis, as well as a clinical predictor for progression to the more severe phenotypic expression to amyloid deposition in the kidney. In one study of amyloidosis in Shar-peis and other breeds, concurrent neoplasia and inflammatory conditions were present in 64% of all dogs (Segev et al 2012). In Shar-pei dogs, amyloidosis is associated with increased levels of serum interleukin-6 in the blood, which is a cytokine that induces the fever response and promotes serum amyloid A secretion (Rivas et al 1992). There may also be increased levels of immunoglobulins and white blood cells (lymphocytes), as a response to the inflammatory process.
2. Intensity of welfare impact
The clinical signs of amyloidosis are a result of kidney failure and vary according to the severity of kidney damage. Small amyloid masses pose no clinical problems but larger depositions cause significant damage to the kidney. Dogs with amyloid deposition in the kidney will generally feel unwell, as impairment to kidney function starts to take place. They may be lethargic and weak, due to both the loss of protein and the build-up of toxic waste products in the blood. Affected dogs have a diminished appetite but with excessive drinking and urination and episodes of vomiting. Some affected dogs have severe gingivitis (inflamed gums), which is painful, and this results in further diminished appetite and subsequent weight loss. Underlying inflammatory disease, such as ‘Shar-pei fever’ can cause painful swelling of the hocks and abdomen, as well as diarrhoea and anorexia.
The condition is progressive, and leads to kidney failure as more healthy tissue is replaced with the amyloid substance. The most common cause of death is severe renal failure (Segev et al 2012) and owners may opt for the dog to be humanly euthanized by a veterinarian before it reaches this end-stage. Dogs can be given symptomatic treatment of chronic kidney failure but there is no specific treatment that can prevent the development of amyloidosis or promote amyloid breakdown. The rate of progression of kidney failure is usually rapid in the late stages of the condition; once an affected dog has developed moderate build-up of waste products in the blood (azotemia and hyperphosphatemia). Underlying inflammatory disease, such as ‘Shar-pei fever’ should be treated appropriately.
3. Duration of welfare impact
Commonly Shar-pei dogs are diagnosed with amyloidosis before 6 years of age, and this is younger than for amyloidosis found in dogs of other breeds. Shar-pei dogs have an earlier onset of being diagnosed with amyloidosis, with a mean age of 4 years (range 2-6 years) compared to other breeds or crossbreeds, which were diagnosed with amyloidosis at or over the age of 7 years (Rivas et al 1993, Segev et al 2012).
The course of familial amyloidosis varies in severity and progression. For some affected dogs, the deposition of amyloid may occur slowly, and kidney function may remain adequate for several years. For others, the deposition of amyloid may be rapid and severe, with kidney failure developing within one year.
4. Number of animals affected
Amyloidosis is rarely reported in the scientific literature, and this may indicate the condition is rare or that it is underreported due to a lack of diagnosis of non-specific clinical signs and the sudden death of the animal before the disease is recognised or diagnosed. Shar-pei dogs have a significantly increased risk of developing amyloidosis, which was 4.5 times higher than the risk of an amyloidosis diagnosis in other breeds or crossbreeds (Rivas et al 1993). In records of renal amyloidosis in veterinary teaching hospitals in Jerusalem and California between 1986 and 2007, renal amyloidosis was diagnosed in 91 dogs, of which 18 were Shar-peis (19.78%; (Segev et al 2012).
5. Diagnosis
Diagnosis is made by identifying amyloid deposits in kidney biopsy samples. Congo red dye is used to stain amyloids in tissue samples in order to accurately diagnose amyloidosis (Linke 2006). However, by the time clinical signs are noticeable, and amyloidosis is suspected, there will have been significant amyloid deposition and associated kidney damage, and therefore diagnosis is often made on post-mortem examination.
6. Genetics
Shar-peis have an inherited predisposition for amyloidosis, and an autosomal recessive trait is suspected (Rivas et al 1993). In a pedigree analysis of Shar-pei dogs with amyloidosis, there were several family clusters in 17 of 24 dogs and these clusters shared a common ancestor within three generations (Rivas et al 1993). The condition affects both males and females, and is therefore is not of sex-linked inheritance (ie autosomal). However, further research is required to identify the number of genes involved in the condition, to distinguish polygenic from single-gene autosomal recessive inheritance.
A recessively inherited trait means that a dog needs to inherit two copies of the mutated gene, ie one from each parent, for it to be affected by the disease. If a dog only has only one copy of the mutation, ie from only one of the parent, the dog will not be affected but will be a carrier, and may pass on the mutated gene to some of their offspring. If two ‘carrier’ dogs, carrying one copy of the mutated gene each, are mated together, 25% of their offspring are likely to be affected and a further 50% will be carriers of the condition.
7. How do you know if an animal is a carrier or likely to become affected?
Genetic tests for identifying Shar-pei fever or amyloidosis in dogs are currently unavailable. Dogs which show recurrent fever of unknown origin or ‘Shar-pei fever’ are thought to be more susceptible to developing amyloidosis. We know that amyloidosis is more prevalent in Shar-peis, and that the disease occurs within families as a recessive trait, which means that some dogs will carry the genetic mutation without being clinically affected. Therefore the relatives and offspring of affected dog are likely to carry the genetic mutations and may produce affected offspring if mated to an affected dog or another carrier.
8. Methods and prospects for elimination of the problem
Although the mode of inheritance of amyloidosis in Shar-pei dogs has been identified, it is not known whether the associated genetic mutation involves only one mutation or a more complex set of multiple genes. Therefore, the advice for elimination of the disease is limited (Meyers-Wallen 2003). In addition to the occurrence of amyloidosis-associated genes, other factors such as infections, inflammatory processes, in particular ‘Shar-pei fever’ are involved in the development of amyloidosis (DiBartola et al 1990). Further genetic testing is required and the development of screening tools to identify dogs that are affected, carriers or unaffected, in order to prevent matings between two affected dogs or two carrier dogs, and matings between carrier and affected dogs, all of which are likely to produce affected offspring. In the interim, it is recommended that breeding from affected dogs is avoided, and from those with affected relatives, including grandparents, siblings, previous offspring and siblings of parents (Farrell et al 2015).
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.
10. References
DiBartola SP, Tarr MJ, Webb DM and Giger U (1990) Familial renal amyloidosis in Chinese Shar Pei dogs.. Journal of the American Veterinary Medical Association 197: 483–7
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
Johnson KH, Sletten K, Hayden DW, O’brien TD, Rossow KD and Westermark P (1995) AA amyloidosis in Chinese Shar-pei dogs: Immunohistochemical and amino acid sequence analyses. Amyloid 2: 92-99
Johnson KH, Westermark P, Sletten K and O’brien TD (1996) Amyloid proteins and amyloidosis in domestic animals. Amyloid 3: 270–289
Linke RP (2006) Congo Red Staining of Amyloid: Improvements and Practical Guide for a More Precise Diagnosis of Amyloid and the Different Amyloidoses. In Uversky VN and Fink AL (eds.) Protein Misfolding, Aggregation, and Conformational Diseases pp. 239–276, Volume 4, Springer US, Boston, MA
May C, Hammill J and Bennett D (1992) Chinese Shar-pei fever syndrome: a preliminary report. The Veterinary Record 131: 586–7
Meyers-Wallen VN (2003) Ethics and genetic selection in purebred dogs. Reproduction In Domestic Animals 38: 73–6
Rivas AL, Tintle L, Kimball ES, Scarlett J and Quimby FW (1992) A canine febrile disorder associated with elevated interleukin-6. Clinical Immunology And Immunopathology 64: 36–45
Rivas AL, Tintle L, Meyers-Wallen V, Scarlett JM, van Tassell CP and Quimby FW (1993) Inheritance of renal amyloidosis in Chinese Shar-pei dogs. The Journal Of Heredity 84: 438–42
Segev G, Cowgill LD, Jessen S, Berkowitz A, Mohr CF and Aroch I (2012) Renal Amyloidosis in Dogs: A Retrospective Study of 91 Cases with Comparison of the Disease between Shar-Pei and Non-Shar-Pei Dogs. Journal of Veterinary Internal Medicine 26: 259–268
Urieli-Shoval S, Linke RP and Matzner Y (2000) Expression and function of serum amyloid A, a major acute-phase protein, in normal and disease sta
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