Q: We have a 2 1/2 year old blue female. She has fevered 3-4 times and had sore hocks once... sore but not swollen. All but on one occasion we took her in to her vet and her blood work showed an elevated white count. I see by reading your website that a raised white count is a sign of FSF as well as the fever. I contacted the breeder and she claims there are 10 pups from several breedings and our dog is the only one that has fevered. I personally contacted an owner of one of our dog’s littermates and her dog did fever once just after receiving her rabies shot. Could this be FSF or just a reaction to the shot? The breeder said that she would contact the owners of all of the pups that came from the breeding and let them know. She said that she would also tell them that she does NOT think it is FSF. Our vet agrees to start her on Colchicine, but many in this group warn of serious if not fatal side affects of this drug. Could you please give your thoughts on the side affects? We had plans to breed and now that probably think that we should not. What are your thoughts on breeding her? If it were true that the other dogs from the same breeding have not fevered would they be as likely as ours to develop amyloidosis? Should they be bred?
A: Well, you certainly covered a lot of the "issues" in one post with your questions! Let me address them one at a time:
As I understand it, your blue girl has had 3-4 fever episodes typical for FSF (I am assuming that she experienced recurrent fever spikes that went away without antibiotics in less than 36 hrs and no other precipitating cause was found on physical exam or on blood work). The breeder says yours is the only pup affected out of 10 but you know that another sibling puppy experienced a fever event after vaccination. (That's 20% - not unexpected if one of the parents is a carrier). Let's talk about post-vaccination fever spikes. Let me state this for the record. It is extremely RARE for non-Shar-Pei puppies to have a fever in the 24-48 hrs after vaccination. I can think of it happening to my knowledge in only a handful of times in the last 25 yrs in all of my non-Shar-Pei patients. It is not uncommon for them to have injection site soreness or be a little "off" for the day after the vaccination and if they do run a fever, it is low-grade. Typical would be 102.8 degrees. Yet, when you talk with some Shar-Pei breeders, they act as if post-vaccination fevers were common and expected – so common and expected that one can't tell the difference between an FSF event and a post-vaccination fever. I hear the same thing about "teething". Teething non-Shar-Pei dogs DO NOT spike fevers. In my opinion, vaccinations –because they are designed to generate an immune response- is a very common trigger for FSF events and is often the first one the FSF patient experiences. It may be the ONLY FSF event that dog experiences and if you ignore this big red flag, you are ignoring the fact that that dog is at high risk for amyloidosis and playing ostrich.
So I can't tell for sure if both puppies meet the criteria for a diagnosis of FSF but it sounds like they probably do. In which case, your breeder is in denial. Colchicine: If she were my patient, I would start her on colchicine according to the guidelines I have posted on my website. I think it is effective and safe in the vast majority of patients and I have experienced no serious side effects and no fatalities in my patients since I started prescribing it routinely in 1993. The worst side effect is diarrhea in some patients that responds to withdrawal of the drug. Diarrhea precedes any other potential more harmful side effects. Because it accumulates in leukocytes, low therapeutic doses are very effective in controlling immune system dysregulation before other organ system dysfunction. Others here have proposed alternatives but colchicine is the only therapy that has been shown to block and possibly even reverse the deposition of amyloid. It is not the silver bullet. The disease that S-P have is more malignant than FMF and we get less predictable control of episodes but I have seen dramatic improvement in most. If I can get them onto the recommended twice-daily colchicine without GI side-effects (and that is most patients), I do think it is working to help prevent amyloidosis. It is used in human FMF patients (a similar periodic auto-inflammatory fever disorder) routinely including safely in pregnant women and lifelong starting in infancy. People with FMF usually died of amyloidosis at around age 40 before colchicine and now live out relatively normal lives. I have not seen any evidence of serious complications of colchicine and no fatalities and I have looked. In my opinion, the worst thing that could happen if you start colchicine therapy is that your dog will not tolerate the drug because of reversible diarrhea and then I would strongly encourage you to explore the alternative therapies being discussed here. You want to find a treatment protocol that will address the underlying on-going pro-inflammatory process and reduce the dog's risk for amyloidosis and treat any fever spikes as they occur.
Breeding: This is a decision only you can make. I personally would not breed a dog that has FSF at this time but I also understand that breeders are between a rock and a hard place and I make no judgments against those that do if they are honest with the people who buy their dogs. If everyone had a hard and fast rule about not breeding any S-P that had any close relatives with FSF/A, there would not be many S-P left in the gene pool. I am not sure that would be a good thing and I think we need to be cautious. We've already seen the results of a profound founder effect in this breed and we don't need to repeat that mistake. Your dog may never develop amyloidosis but you are correct that there may be other pups in the litter that are at risk and may die prematurely of kidney or liver failure even if they never exhibit a fever event.
My Take on Amyloidosis
Dana Hoogland, 2006
Amyloidosis is not caused directly by a genetic defect.
So why does amyloidosis occur and what role does inheritance play?
This phenomenon occurs when a build up of inflammatory factors start to affect the metabolism of acute phase lipids of which serum Amyloid A is one component part. This change in metabolism alters the way serum amyloid A is cleaved (separated from the lipid HDL (high density lipoprotein) it is joined during an acute phase response). This malfunction modifies the molecular shape of the serum Amyloid A protein. This change in its molecular proportions delays its complete degradation and removal from the system. These partially degraded proteins are highly toxic to the system and fibrillation is part of the system for removing the toxic partially degraded proteins. It has been found that fibrils are not specifically toxic compared to the unbound partially degraded serum Amyloid A protein. The extraordinary amount of partially degraded Serum Amyloid A and its continued presence is what causes the increase in fibrilar material in the extracellular space in organs throughout the body.
So in a sense amyloidosis, which means the deposition of fibrils, is not the actual disease mechanism but a way of the body to get ride of the toxic pre-fibrilar material (not yet fibrils) that poison the system. These fibrils will be removed from the system once the amount of serum amyloid A production no longer exceeds the body’s ability to eliminate its toxic degradation products. This action of the body to remove these partially degraded proteins is not a genetic malfunction and it therefore follows that all types of amyloidosis occur due to this same mechanism and although the instability of some precursor proteins in some type of amyloidosis do have a genetic background, the type of amyloidosis found in Shar-pei is caused by the inflammatory processes. What I mean with some instable precursors in some type of amyloidosis is indeed having a genetic background is because these production of these proteins malfunctions and this effects the way they are metabolized. Some amyloidosis have a genetic component because of a malfunction in the formation of the protein and that makes them unstable and improperly metabolized. Why is this not so for Serum Amyloid A? Because the Serum Amyloid A that is produced by people and animals that do not have amyloidosis is of the same conformation as that seen in those that do have this malfunctioning metabolism and subsequent systemic reactive amyloidosis. There is no difference in the production of this protein that causes the change in this metabolism and the metabolism change in itself is also not due to a genetic malfunction as it can be induced in all macrophages (cells that metabolize Serum Amyloid A) derived from different donors with or without inflammatory diseases meaning that even in people not predisposed this disease would be able to occur.
It is therefore my profound opinion that amyloidosis is not a genetic disease in Shar-pei but then what causes this disease to be so extremely common in this breed? Because these changes to this protein’s metabolism do not occur if there are no prolonged inflammatory cascades the inheritance factor of this disease lies within the inflammatory diseases that are prevalent in this breed. The most dominant one is, of course, FSF.
FSF is not what most people think, it is not only a fever disorder. The fever is only a symptom of the disorder and the disorder can therefore be present even without fevers. FSF is an auto-inflammatory disease, which means that it invokes inflammatory cascades. These processes can also induce fevers but it is not the fever that causes the release of acute phase proteins. They are actually both caused by the release of the same inflammatory mediator as the interleukin 6. It is, therefore, when you would test for this cytokine at the time of a fever it would be high (this has been indicated by previous studies and is will be now investigated again in the current study). This is not specific for the inflammatory disease seen in Shar-pei as most chronic inflammatory disease carry this feature and therefore display many common symptom patterns but this is also why many different types of inflammatory diseases can lead to amyloidosis as a secondary complication (not because all these people or even animals have a genetic predisposition to develop amyloidosis). The absence of fever does not mean that these processes are not present (the current study at Colorado State University and previous studies at Cornell already have proven this to be true as many dogs within the FSF group have inflammatory mediator levels that are high even in the absence of a fever episode) but also the opposite is true besides during the fever episodes these processes can be absent. Therefore a dog can fever at regular intervals and not develop amyloidosis because the inflammatory cascades are not persistent enough to cause this change in metabolism or it doesn’t continue long enough so that the amount of formed instable proteins is very low and will not result in enough fibrilar material to be detected. Also the same is true that sometimes a dog will never show an obvious symptom for the owner to know that the inflammatory processes are present and the dog will die of amyloidosis without ever showing a specific fever episode. This is what made the Shar-pei community think the FSF and amyloidosis are not related but this is a false assumption which originated out of the believe FSF is a fever disorder and nothing more than that. It is not, fever is a symptom of that disorder but this disorder can be asymptomatic as well but still have sufficient inflammatory activity to cause amyloidosis. Also the idea that because dogs can fever all their lives without developing amyloidosis is not an indication that amyloidosis is therefore a separate entity with its own genetic background. It is very simple: without inflammatory cascades there is no AA amyloidosis.