Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

SiameseSiamese

Amyloidosis

Related terms: generalised amyloidosis; hepatic amyloidosis

VeNom term: Amyloidosis (VeNom code: 383).

Related conditions: Chronic inflammation; chronic liver failure; spontaneous liver haemorrhage

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 Siamese cats, there is significant amyloid deposition in the liver, which leads to decreased function, and fatal liver failure can occur. The clinical signs of amyloidosis are related to progressive liver damage, and include dehydration, poor coat quality, pale or yellow mucous membranes, gingivitis (inflammation of the gums) excessive drinking and urination, lethargy, lack of appetite (inappetance) and weight loss. Amyloids deposits in the liver can lead to rupture and spontaneous internal bleeding, which requires emergency treatment to save life.

Commonly cats with the condition develop amyloidosis between 1 and 5 years of age, although the progression of the disease in variable. For some affected cats, the deposition of amyloid may occur slowly, and liver function may remain adequate for several years. For others, the deposition of amyloid may be rapid and severe, with liver failure developing within one year.

Amyloidosis in cats is rarely reported in the scientific literature, and the mode of inheritance is not known. This may indicate the condition is rare or that it is underreported due to a lack of diagnosis. Amyloidosis is more prevalent in Siamese cats than in most other breeds, and the trait is inherited within families. It is therefore recommended that breeding from affected cats is avoided, and from those with severely 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, which is formed in the liver.

In Siamese cats, amyloids derived from serum amyloid A are primarily deposited in the liver, and to a lesser extent, other tissues such as the spleen, stomach, intestines, thyroid, kidney 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 liver in cleaning the blood of toxins, metabolism and protein synthesis. The liver becomes enlarged, inflamed and unable to function as normal. As the disease progresses, there is more damage to the liver as more liver tissue is replaced with amyloid filbrils. Over time the liver stops functioning normally and eventually this causes liver failure, which is fatal. Amyloids deposits in the liver can lead to rupture and spontaneous internal bleeding, which requires emergency treatment to save life. The clinical signs of amyloidosis are related to progressive liver damage, and include dehydration, poor coat quality excessive drinking and urination (polydipsia, polyuria), lethargy, inappetance and weight loss).

2. Intensity of welfare impact

The clinical signs of amyloidosis are variable in accordance with the severity of liver damage. Cats with significant amyloid deposition in the liver will generally feel unwell, as damage starts to take place. They may be lethargic and weak, and may experience abdominal pain. Affected cats have a diminished appetite but with increased drinking and urination and episodes of vomiting and diarrhoea. Some affected cats will have severe gingivitis (inflamed gums), which is painful, and this will result in further diminished appetite and subsequent weight loss.  

The condition is progressive and untreatable, leading to liver failure as more healthy tissue is replaced with the amyloid substance. Cats can be given symptomatic treatment for chronic liver failure in the early stages of the condition, although treatment is not always successful in managing the clinical signs. 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).

3. Duration of welfare impact

Commonly cats develop amyloidosis between 1 and 5 years of age, although the progression of the disease in variable. For some affected cats, the deposition of amyloid may occur slowly, and liver function may remain adequate for several years. For others, the deposition of amyloid may be rapid and severe, with liver failure developing within one year.

4. Number of animals affected

Amyloidosis in cats 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/or death before the disease is recognised or diagnosed. Siamese cats are more susceptible to the condition compared to most other breeds.

5. Diagnosis

A diagnosis can be made by identifying amyloid deposits in liver biopsy samples. By the time clinical signs are noticeable, and amyloidosis is suspected, there will have been significant amyloid deposition and associated liver damage, and therefore diagnosis is often made on post-mortem examination.

6. Genetics

Amyloidosis is a genetically inherited disease that occurs within families in Siamese cats (ie a familial trait). Siamese cats have a genetically different version of serum amyloid A – which is more likely to form amyloid fibrils - compared to other breeds that have a low susceptibility for amyloidosis. However, the mode of inheritance in currently unknown, and further research is required to determine how these genes and amyloidosis susceptibility are inherited in cats.

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

A genetic test for identifying amyloidosis in cats is currently unavailable. We know that amyloidosis is more prevalent in Siamese cats than most other breeds, and that the trait occurs within families, therefore the relatives and offspring of affected cats may be likely to carry the genetic mutations which predispose them to developing amyloidosis.

8. Methods and prospects for elimination of the problem

Although the genes involved in amyloidosis in Siamese cats have been identified, the mode of inheritance not known and there are other factors such as infections and inflammatory processes are involved in the development of amyloidosis. Further genetic testing is required and the development of screening tools to identify cats that are likely to become affected. In the meantime, it is recommended that breeding from affected cats is avoided, and from those with severely 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

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. 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 cytokines 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 (Johnson et al 1996). 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.

In Siamese cats, amyloids derived from serum amyloid A are primarily deposited in the liver, and to a lesser extent, other tissues such as the kidney, stomach, intestines, thyroid and heart (van der Linde-Sipman et al 1997). These amyloids are more difficult for the body to break down than normal proteins and so build up and displace healthy tissue, disrupting the normal processes of the liver in cleaning the blood of toxins, metabolism and protein synthesis.

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 caused by the build up of amyloids means that liver become enlarged, inflamed and cannot function adequately and may eventually fail to function at all. Amyloids deposits can also cause the liver to become fragile, and it may rupture with spontaneous internal bleeding (haemorrhage; van der Linde-Sipman et al 1997, Godfrey & Day 1998), which can lead to death. The clinical signs of amyloidosis are related to chronic liver failure (van der Linde-Sipman et al 1997), and include anorexia, depression, weakness, fatigue, weight loss, vomiting, diarrhoea, excessive drinking (polydipsia) and excessive urination (polyuria). Some cats may present with abdominal pain. There may be poor coat quality, and gingivitis (inflammation of the gums). 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.

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2. Intensity of welfare impact

The clinical signs of amyloidosis are a result of liver failure and vary according to the severity of liver damage. Small amyloid masses pose no clinical problems but larger depositions cause significant damage. Cats with amyloid deposition in the liver will generally feel unwell, as impairment to the liver 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 product in the blood and may experience abdominal pain. Affected cats have a diminished appetite but with excessive drinking and urination and episodes of vomiting and diarrhoea and weight loss. Liver rupture and spontaneous haemorrhaging may cause acute pain and require emergency treatment to save life.  

The condition is progressive, and leads to liver failure as more healthy tissue is replaced with the amyloid substance. Cats can be given symptomatic treatment of chronic liver failure but there is no specific treatment can prevent the development of amyloidosis or promote amyloid breakdown. Underlying inflammatory disease is not commonly detected, but any concomitant infections should be treated appropriately. 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).

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3. Duration of welfare impact

Commonly cats develop amyloidosis between 1 and 5 years of age (Paltrinieri et al 2015). In Siamese cats, the average (mean) age of diagnosis was 3.5 years (van der Linde-Sipman et al 1997). The course of familial amyloidosis varies in severity and progression. For some affected cats, the deposition of amyloid may occur slowly, and liver function may remain adequate for several years. For others, the deposition of amyloid may be rapid and severe, with liver failure developing within one year.

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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. During a 7-year period (1987-1994), 27 of 2176 cats of varying breeds were diagnosed with amyloidosis, but the frequency of amyloidosis diagnosis in Siamese cats was markedly high (12 of 194 Siamese cats; 6.2%; van der Linde-Sipman et al 1997).

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5. Diagnosis

Diagnosis is made by identifying amyloid deposits in liver biopsy samples. Congo red dye is used to stain amyloids in tissue samples in order to accurately diagnose amyloidosis (Linke 2006). A high level of urinary excretion of serum amyloid A may be useful to detect amyloidosis before the onset of clinical signs (Paltrinieri et al 2015). However, by the time clinical signs are noticeable, and amyloidosis is suspected, there will have been significant amyloid deposition and associated liver damage, and therefore diagnosis is often made on post-mortem examination.

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6. Genetics

Amyloidosis is a genetically inherited disease which occurs within families in Siamese cats (ie a familial trait). Analysis of the pedigrees of 9 Siamese cats with amyloidosis showed that they were inter-related (van der Linde-Sipman et al 1997). The higher incidence of amyloidosis in Siamese cats than in other breeds may be linked to differences in the amino acid sequence of the amyloid protein A. In the Siamese breed, the protein AA was found  to have two amino acid substitutions, differing from AA-proteins in other breeds such as the Abyssinian (Niewold et al 1999), and this may explain the different tissues involved in these two breeds (ie renal in Abyssinian versus hepatic in Siamese cats). However, the mode of inheritance in currently unknown, and further research is required to determine how these genes and amyloidosis susceptibility are inherited in cats.

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

A genetic test for identifying amyloidosis in cats is currently unavailable. We know that amyloidosis is more prevalent in Siamese cats than in most other breeds, and that the disease occurs within families, therefore the relatives and offspring of affected cats may be likely to carry the genetic mutations which predispose them to developing amyloidosis..

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8. Methods and prospects for elimination of the problem

Although the genes involved in amyloidosis in Siamese cats have been identified, the mode of inheritance not known, and therefore 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 and inflammatory processes are involved in the development of amyloidosis (Rossum et al 2004). Further genetic testing is required and the development of screening tools to identify cats that are likely to become affected. In the interim, it is recommended that breeding from affected cats is avoided, and from those with severely affected relatives, including grandparents, siblings, previous offspring and siblings of parents (Farrell et al 2015). 

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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

 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

Godfrey DR and Day MJ (1998) Generalised amyloidosis in two Siamese cats: spontaneous liver haemorrhage and chronic renal failure. Journal of Small Animal Practice 39: 442–447

Johnson KH, Westermark P, Sletten K and O’brien TD (1996) Amyloid proteins and amyloidosis in domestic animals. Amyloid 4: 270-289

van der Linde-Sipman JS, Niewold TA, Tooten PCJ, de Neijs-Backer M and Gruys E (1997) Generalized AA-amyloidosis in Siamese and Oriental cats. Veterinary Immunology and Immunopathology 56: 1–10

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

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

Niewold TA, Linde-Sipman JS van der, Murphy C, Tooten PCJ and Gruys E (1999) Familial amyloidosis in cats: Siamese and Abyssinian AA proteins differ in primary sequence and pattern of deposition. Amyloid 6: 205-209

Paltrinieri S, Sironi G, Giori L, Faverzani S and Longeri M (2015) Changes in Serum and Urine SAA Concentrations and Qualitative and Quantitative Proteinuria in Abyssinian Cats with Familial Amyloidosis: A Five-year Longitudinal Study (2009-2014). Journal of Veterinary Internal Medicine 29: 505–512

Rossum M van, Asten FJ van, Rofina J, Lenstra JA, Benson MD and Gruys E (2004) Analysis of cDNA sequences of feline SAAs. Amyloid 11: 38-43

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 states. Current Opinion in Hematology 7: 64–9

© UFAW 2016


Credit for main photo above:

By Karin Langner-Bahmann, upload von Martin Bahmann (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html)  or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons