Q: Are FSF and Amyloidosis two separate diseases?
A: First you need to think about the disorder underlying FSF (familial Shar-Pei fever). We tend to focus on the fevers because they can be so dramatic but it is the tip of the iceberg so-to-speak. S-P with FSF have an immune system that is over stimulating their body's immune system - it is classed as an "auto-inflammatory" disorder rather than "auto-immune" disorder because it impacts at a much earlier and more basic state and stimulates ancient pathways of inflammation rather than just antibodies. I call it "immune dysregulation" rather than true immunodeficiency because actually there is "too much" and that leads to an inability to respond normally. Balance is needed - yin and yang.
What we know is that one of the main chemical messengers of inflammation that trigger the acute phase reactant proteins (APP) which are the precursors of amyloid - is Interleukin-6 (IL-6). This is a cytokine: a chemical messenger of inflammation. We have found that S-P with FSF have chronically elevated background levels of IL-6 in significantly greater numbers than S-P with no evidence of FSF or no close relatives with FSF. Unfortunately not every S-P with FSF has the elevation when tested so we can't use it as a definitive screening test.
From article on amyloidosis that I wrote for the CSP Charitable Trust and posted there and on my website, the paragraph "Why do some Shar-Pei with FSF get Amyloidosis and others do not?":
We are speculating that it is probably due to variables in the degree of APP in the dog's bloodstream - some dogs may have mild levels and others severely elevated amounts which may overwhelm their ability to eliminate them entirely. In humans with periodic fever disorders, it is believed that there may be a linked mutation that prevents the normal elimination of the by-products the APP leading to amyloidosis in some patients. I suspect both factors are important in the development of amyloidosis in Shar-Pei.
FSF and Amyloidosis are closely linked and FSF is a huge risk factor for developing Amyloidosis. However, not every Shar-Pei with recurrent fevers from FSF will develop Amyloidosis. FSF does NOT always lead to early death from amyloidosis and some patients suffer recurrent fevers all their lives and are negative by CRS for amyloidosis at 12 yrs of age or older. These dogs are the exception, not the rule. These dogs might be heterozygous for the disorder – "carriers" – as it has been observed repeatedly that if bred to another similar "carrier", their offspring will often manifest with amyloidosis. We will be looking closely at this in our studies with Drs. Avery and Kastner's laboratories.
Dogs with the underlying disorder causing chronic elevations in the APP do not always manifest a fever before presenting with signs of amyloidosis. This is observed with the human periodic fever disorders as well. This is why the fever is a marker for risk. The fevers don't CAUSE the amyloidosis. There is no association between frequency and severity of fevers and resultant amyloidosis. A S-P with just one fever or just a couple when young is just as likely to get amyloidosis as the dog that fevers every 7-10 days or has recurrent fevers > 106 degrees.
To put this in perspective, I have seen hundreds of Shar-Pei in the last 20 yrs die of amyloidosis, confirmed by pathologic exam, in my own practice. I have had one case of amyloidosis in an 11 yr old non-Shar-Pei dog. Amyloidosis in non-Shar-Pei dogs is a very rare event and occurs in much older dogs. Another characteristic that can differentiate between the two is that most S-P will get medullary (the inner part of the kidney) and other dog breeds routinely get glomerular (the outer cortical part) amyloid. Abyssinian cats also have an inherited form of amyloidosis and get medullary amyloid like Shar-Pei.
I have seen FSF episodes but not amyloidosis (as of this date) in Shar-pei mixed breed dogs. So they are inextricably linked (at this time) but I don't consider them one and the same.
Q: Should dogs with FSF be used in a breeding program?
A: The simple answer is "no" but life is never simple. I bred my last litter (before the China dogs) in 1987 because after that I realized that I couldn't give any reasonable assurance that a particular puppy would not die prematurely of some terrible disease. The randomness of the early deaths in Shar-Pei is horrible. I did however have the alternative of choosing to continue to work with the breed as a veterinarian – indulging my love for the dogs and staying involved that way. If all the breeders with honesty and integrity quit breeding, the only S-P left being bred would be those dogs from the naive, dishonest and/or unscrupulous.
At the AKC Canine Health Foundation conference in St. Louis last Fall, one of the premier geneticists warned the group about eliminating all dogs with one particular genetic fault from their gene pool because sometimes the mutation is linked to the best characteristics of what makes that breed unique. He cautioned us to move slowly so that we did not throw the baby out with the bath water as DNA tests became more prevalent and routine. Every individual has to make this choice for him or herself. But we need better diagnostics so we can make informed choices.
I can empathize with your reluctance to produce another litter in the midst of such uncertainty. It can break your heart to know that you've inflicted such suffering on a family - those phone calls tear you apart. I tell breeders IF they are going to breed S-P they have to know their pedigrees inside and out and be aware of the tendency for amyloidosis to skip a generation. Try never to breed two known affected or carriers to each other. Even doing this, you may encounter amyloidosis because so many dogs just don't show any signs or they are missed or excused (a teething fever, etc.)
Cancer: I would be careful with lines with an inordinate amount of Mast Cell or Lymphoma since these two cancers seem to have a heritable component in Shar-Pei and do your very best to steer clear. I do think their immune dysregulation is involved in their predilection for these two cancers.
Q: I have a 2-year-old Shar Pei. I recently found out that his mother died of amyloidosis. So, from what you wrote above, does this mean that he has less of a chance of getting amyloidosis because it tends to skip a generation? Also, I was wondering if you've ever heard of germanium being used to prevent amyloidosis? There were some articles on the web a homeopath found stating this. Have you ever heard of this or looked into it? My Shar Pei does have FSF/SHS - I treat him with homeopathic remedies & naturopathic supplements. He has been fever free for 4 months being on these. I also would like to ask you what you think of a raw diet?
A: I should have been clearer on that - when you breed a dog with amyloidosis, our examination of the pedigrees suggested that all the offspring were at least carriers but did not necessarily die of amyloidosis unless the other parent was also a carrier or also had amyloidosis. I was speaking about carrier X carrier or breeding two dogs that you don't suspect have the disease.
As I stated above, I am not an experienced practitioner of homeopathy and can't advise you pro or con. I am open to its use and willing to learn. But I believe allopathic medicine and homeopathy are usually mutually exclusive and since I don't have enough knowledge or education in that area, I don't recommend it to my patients. I can only give you my experience and knowledge - and I would welcome all of yours. Dr. Jeff Vidt and I have the advantage of having seen thousands of Shar-Pei over the last 25 yrs - most veterinarians never come close. The big advantage for me is knowing what is uniquely normal for them and what their disease process often presents as in the earliest stages. Shar-Pei have made me a much better veterinarian but I'd wish that many of those lessons had not been so very painful for all involved.
Re: raw diets – that’s a long topic and I'll give you my thoughts about that if time permits. First, define "raw diet" VBG
There's a huge variation in what people are thinking of when they say that. I'm drying a batch of eggplant downstairs at low temperatures - one of the advantages of low temperature drying of foods as a method of preservation is that it preserves much of its integrity as a "raw food".
Q: Can only Congo Red staining can differentiate amyloidal deposits?
A: "All amyloid deposits stain with Congo Red and have a characteristic green color with birefringence under polarized light. Of the many types of amyloidosis which stain with Congo Red only reactive amyloid and beta-2 microglobulin amyloid are decolorized by potassium permanganate oxidation."
Q: How do we "split" amyloid deposits from other types of amyloidosis; or does it matter? I'm asking is amyloidosis, amyloidosis: and we're wasting our money on a Congo Red Stain?
A: In severe cases, the amorphous pink amyloid substance may be obvious to the pathologist on microscopic exam even under normal stains without CRS but submitted tissues cannot be said to be "negative for amyloidosis" unless the Congo red is used. There is no way to differentiate generalized reactive systemic amyloidosis from the inherited form in Shar-Pei except by its unusual medullary pattern and the young age of the dog but "regular" non-Shar-Pei amyloidosis is so rare, it should not be a real concern. The issue is missing it if you don't use Congo red.
Q: Okay, given your newest article about the IL-6 levels, I have this question: Can we test our dogs for IL-6 to see if they are elevated? I know all that would tell us is whether are dogs are in the statistically significant group and not a positive or negative.... but hey, wouldn't mind knowing.
I understand that you are asking for dogs that are fevering for sending in the samples for the research project. I am asking about inquiring into finding out my dogs IL-6 and seeing if it was high or not to determine if they are in the group with A/FSF related....... or not. I thought if you are testing fevering dogs, then those dogs are all affected. I am thinking that you would have to have samples from 'other' dogs in order to make the comparison and the statements about statistical significance.
Preliminary results have shown that a statistically significant greater number of Shar-Pei with FSF or Shar-Pei with close relatives with FSF/A have elevated background levels of IL-6. Shar-Pei without evidence of FSF and no close relatives with FSF/A did not have statistically significantly elevated background levels of IL-6.
A: We are still looking but right now it looks like not every dog with FSF has elevated levels at the time of testing. The group of S-P that had a known history of fevers along with those dogs that had close relatives diagnosed with FSF had much higher levels of IL-6 statistically than those that did not. But I do not think this is going to be our survey test. I'm hoping for something a lot more definitive and work is on going. These results simply confirmed the results I published with Drs. Rivas and Quimby in 1992.
Rivas A L, Tintle L, Kimball E S, Scarlett J, Quimby F.A. Canine
Febrile Disorder Associated with Elevated Interleukin-6. Clin Immunol
Ceron J J, Eckersall P D, Martinez-Subiela S. Acute Phase Proteins in Dogs and Cats: Current Knowledge and Future Perspectives. Vet Clin Path (2005)34/2:85-99
From the introductory opening paragraphs:
"General Concepts of the Acute Phase Response
The acute phase response refers to a nonspecific and complex reaction of an animal that occurs shortly after tissue injury. The origin of the response can be attributable to infectious, immunologic, neoplastic, traumatic or other causes, and the purpose of the response is to restore homeostasis and to remove the cause of its disturbance. The acute phase response is considered a part of the innate host defense system, which is responsible for the survival of the host during the critical early stages of an attack, and in evolutionary terms, it predates the acquired immune response.
The acute phase response is characterized by a number of different systemic effects, including fever, leukocytosis, increased blood cortisol and decreased thyroxine concentrations, metabolic changes (i.e. lipolysis, gluconeogenesis, muscle catabolism), and decreased serum iron and zinc concentrations. The response also includes changes in the plasma proteins, called acute phase proteins (APPs), some of which decrease in concentration (negative APPs; e.g., albumin or transferring) and others which increase in concentration (positive APPs; e.g., C-reactive protein [CRP], serum amyloid A [SAA], haptoglobin [Hp], alpha-1-acid glycoprotein [AGP], ceruloplasmin [Cp], and fibrinogen). Most positive APPs are glycoproteins synthesized mainly by hepatocytes upon stimulation by proinflammatory cytokines and released into the bloodstream.
The main proinflammatory cytokines are interleukin (IL)-6, IL-1, and tumor necrosis factor (TNF)-alpha. In humans, IL-6 is also considered one of the most important cytokines able to induce synthesis of different APPs either directly, such as Hp, or combined with IL-1, as in the case of CRP and SAA, and serum levels of IL-6 markedly increase during and acute phase response in dogs. Cytokine assays could be used for quantifying the induced systemic response to infection or inflammation; however, the assay of APPs has been proposed as a robust alternative for this purpose."
What this scientific review does is describe the importance of the APP in dogs and cats. Shar-Pei have a familial auto-inflammatory disorder called Familial Shar-Pei Fever (FSF) associated with chronically elevated background levels of IL-6 which predisposes them to Amyloidosis. This article helps explain why we see fever and a frequently elevated white blood count in these patients and may offer some explanation for why we sometimes see Cushing's-like signs in these dogs and why hypothyroidism is not uncommon. It may also explain some of their chronic anemia and skin problems. IL-6 is a potent inducer of the APP and since amyloidosis can occur secondary to the body's inability to completely breakdown and eliminate the large quantities of APP, it offers explanation for why FSF and Amyloidosis are frequently linked.
Dr. Avery's laboratory at Colorado State University's Veterinary College is currently working on quantifying and describing the APP profile of dogs with and without signs of FSF with a grant being funded and supported by many of you through the Chinese Shar-Pei Charitable Trust (www.cspcharitabletrust.org) and the AKC Canine Health Foundation.