Amyloidosis , Swollen Hock Syndrome, Shar-Pei Fever

FAMILIAL SHAR-PEI FEVER AND FAMILIAL AMYLOIDOSIS
OF CHINESE SHAR-PEI DOGS

Linda J. M. Tintle, DVM (Reprinted from March/April 1997 BARKER)

SHAR-PEI WITH FSF
Have one or more bouts of unexplained fever, usually 103-107 degrees F(39.4-41.7 C) but rare cases may go higher. If they don't have a fever it is not FSF. (Assuming not on colchicine). Fevers usually start before they are 18 months old but adult onset attacks are not uncommon. Fever episodes usually become less frequent with age. Fever episodes last 24-36 hours in most cases without treatment. Of the dogs that experienced fevers, approximately 53% had experienced

SWOLLEN HOCK SYNDROME (SHS) at some time along with the fever
Be very careful not to mistake the normal"socks" (excess wrinkling around the hocks on some Shar-Pei) for SHS. Fever episodes may be accompanied by one or more of the following signs:Swelling around a joint (cellulitis) with or without inflammation of the joint itself. One or more joints may be affected but most cases involve the tibiotarsalor "hock" joint (SHS).Sometimes a swollen, painful muzzle. Abdominal pain, reluctance to move, "roached" back, mild vomiting or diarrhea, shallow rapid breathing. An autosomally recessive inherited disorder of humans. Characterized by recurrent bouts of fever, usually starting in childhood. Polyserositis (inflammation of the thin membranes that line certain cavities of the body...joints, abdomen, chest, etc.) resulting in abdominal, chest and joint pain, usually involving the knee or ankle. Swelling inflammation of the skin about the ankle or top of foot. Free from symptoms between attacks. May develop amyloidosis.

SHAR-PEI WITH FSF HAVE ABNORMALLY HIGH LEVELS OF ACYTOKINE CALLED INTERLEUKIN-6 (IL-6)
IL-6 turns on various parts of the immune system. It is involved in controlling the fever response and is a trigger, alone or with other cytokine, for the production of the acute phase reactant proteins (APP) or inflammation...theprecursors of Amyloid AA. Chronically elevated levels of IL-6 leads to chronically elevated levels of the APP. The APP are normally produced during active inflammation. The healthy animal breaks down the APP soon after the injury or disease and the toxic wastes are excreted from the body. Amyloidosis occurs when the APP can not be broken down normally by the animal because ofa defect or when a large amount of APP continuously overwhelms the body's ability to get rid of it. Amyloid is then deposited outside the cell walls and not eliminated from the body. The build-up of the waste product amyloid is what causes disease. Amyloid compresses the adjacent cell walls causing cell damage or death. Amyloid is deposited throughout the body and may be detected in many different organs and in blood vessels. In the kidneys, the damage is irreversible and usually results in kidney failure and subsequent death of the dog.

INHERITANCE OF FSF AND AMYLOIDOSIS IN CHINESE SHAR-PEI
Published research indicates that this trait is compatible with an autosomal recessive inheritance. AL Rivas, L. Tintle, JM Scarlet, C van Tassel & F.W.Quimby JOURNAL OF HEREDITY 1993;84:438-442.-My personal opinion, based on my experience and pedigree analysis, is that heterozygous carriers may (or may not experience fevers +/-SHS but do not die prematurely from amyloidosis. I believe the homozygous animals (which usually but not always experience fevers +/-FSF) are the ones dying prematurely from amyloidosis. Private communication with many of the original breeders and importers of these dogs has led me to believe that many of them were affected by this immune system dys-regulation. Since all lines go back to this same small genetic pool of dogs, it is not surprising that the problem is widespread throughout the breed and throughout the world.-In people with "Phenotype II" FMF, signs of amyloidosis may precede outbreaks of fever or the patient may never experience or report any fever episodes. This unfortunately occurs in Shar-Pei as well. Generally, FSF episodes should be considered to be an important marker that the dog is extremely high risk to develop amyloidosis and should be carefully monitored.

AMYLOIDOSIS = KIDNEY FAILURE OR, LESS COMMONLY, LIVER DISEASE/FAILURE.

AMYLOIDOSIS IS A KILLER
Deaths have been reported to me as young as eight months of age and as old as twelve years of age. It most commonly strikes between three and five years of age. Amyloidosis can only be diagnosed by surgical biopsy or tissues obtained at autopsy. The abnormal amyloid protein is identified with special stains when examined under the microscope.

FREQUENCY OF FSF
A survey done at the 1991 CSPCA National Specialty and data from records at my own and Dr. Jeff Vidt's practice suggests that the incidence of FSF in Shar-Pei is about 23-28% affected.

HOW IS FSF DIAGNOSED?
No single test yet available. Still a diagnosis of excluding the other possibilities. Blood test are usually negative/normal except that an elevated white blood count with a left shift in not uncommon as is a mildly elevated alkaline phosphatase level.

I PERFORM THE FOLLOWING MINIMUM DATABASE ON PATIENTS WITH POSSIBLE FSF:
Complete blood count(CBC) with differential, serum chemistry panel,complete urinalysis (UA). I also routinely recommend these tests on all bitches prior to breeding and studs at least annually! There are few worse horrors for a breeder than having the stress of pregnancy cause a bitch to go into kidney failure and die before the pups are a few weeks old and then having to raise a litter of orphan puppies which you know are carrying the gene for amyloidosis. Lyme Disease (Borreliosis) and other tick borne diseases should be ruled out in endemic areas. If UA suggests an increased amount of protein is being lost in the urine, I recommend a urine protein to creatinine ratio be run on the urine. Most Shar-Pei have medullary amyloid may or may not have proteinuria (unlikehumans) but proteinuria is always a significant finding. Loss of ability to concentrate urine (specific gravity consistently 1.01 to 1.022) is a more common early indicator of a problem. Immune panels, joint taps, radiographs, cultures, immunoglobulin levels and other diagnostic procedures are sometimes needed in individual cases. Research is currently being conducted at the University of Missouri by Dr. Gary Johnson and staff to attempt to identify the genetic defect associated with FSF/Amyloidosis in Chinese Shar-Pei. This research is being supported by contributions tot he CSPCA Charitable Trust, c/o Lee Arnold, Chairman, P.O. Box 7007, Bedminster, NJ 07921 U.S.A. The gene for FMF was located on human chromosome 16 and efforts are centering on finding a similar defect in the equivalent are of the canine genome. A DNA test should accurately differentiate between normal, affected and carrier animals whether have experienced fever episodes or not. We desperately need this test!

TREATMENT OF FSF EPISODES
Tender loving care, close observation of body temperature and otherwise benign neglect.* Buffered aspirin.* 50% Dipyrone, Banamine (flunixin meglumine) to reduce fever and provide pain relief. * Extremely high fevers or other evidence of severe systemic inflammatory response syndrome (SIRS) may indicate that rapid aggressive IV fluid therapy and shock treatment is necessary in some very rare cases. FSF episodes can be fatal and should never be shrugged off as inconsequential.* There is no infection. Therefore, antibiotics are unnecessary unless the veterinarian is concerned that the stressed dog may be secondarily infected.* Recently, a few cases of severe pustular dermatosis with high fevers and vasts loughing of skin have been reported to or seen by Dr. Jeff Vidt and myself. These seem to resemble the "flesh eating" Streptococcus infections reported in humans and require aggressive antibiotic and supportive treatment. These can be fatal even with treatment. We would appreciate hearing about any new cases.

COLCHICINE
Used in humans for over 400 years and most commonly used as the treatment for gout. * Used in FMF patients to reduce the frequency and severity of painful fever episodes and prevent the development of amyloidosis.* Before colchicine therapy, up to 30% of all FMF patients died prematurely(usually around age 40) of amyloidosis.* I currently recommend the use of colchicine prophlactictically in any Shar-Pei which I believe to have FSF as soon as I am convinced that this is what the dog has. I do not recommend waiting until evidence of disease due to amyloidosis is seen. At that point, it is almost too late.* We have some Shar-Pei on colchicine for over four years and I have yet to see evidence of serious side-effects other than gastro intestinal disturbances (diarrhea +/- vomiting) which resolve when the drug is withdrawn. Some dogs are, however, unable to tolerate the drug because of associated diarrhea. Others seem to tolerate a reduced dosage.* In FMF treatment, the drug has been shown to be safe in children as young as three years of age, in pregnant women and when given lifelong. Fatalities associated with massive overdose have been due to bone marrow suppression. I have monitored CBC's in my patients and have not seen evidence of bone marrow suppression but this should always be kept in mind.* I recommend once daily treatment for two weeks and if no gastrointestinal problems have occurred, I double the dose to twice daily. I will provide a lengthy treatment protocol with pertinent scientific references to any veterinarian upon request.* I personally believe that this drug works in this disorder and is the best treatment option currently available. I would like to see double-blind controlled studies done to prove this. So far, no research has been conducted/funded to do so but I have kept careful records and Dr. DiBartola at Ohio State University who did the original studies on amyloidosis in Shar-Pei has expressed an interest in overseeing such a study.* Dogs on colchicine may continue to experience some fever episodes. Some cease completely. Others commonly report a decrease in severity and frequency. Some owners report SHS without fever. I believe the colchicine works in dogs as it does in people; the control of the fevers and the blocking of amyloid deposition are by two different pathways and ongoing fevers are not evidence of worsening amyloidosis.

THERE IS NO ASSOCIATION BETWEEN THE NUMBER, FREQUENCY AND SEVERITY OF THE FEVER EPISODES AND THE DEVELOPMENT OR DEGREE OF AMYLOIDOSIS.
A dog that experiences on single fever episode in his entire life is just as likely to get amyloidosis as the dog that gets them every seven to ten days. They should be considered a marker for high risk for the disease. This is also why I do not recommend waiting to see if they ever get another one!

MOST COMMON SIGNS OF ADVANCED AMYLOIDOSYS
* Unexpected weight loss.* Increased thirst and frequency of urination.* Vomiting.* "Bad Breath" as a result of uremia (the buildup of toxins/wastes in the blood stream as the kidney +/- liver fails to process them).

HOW IS AMYLOIDOSIS TREATED?
Slow the progression of irreversible kidney disease with dietary management and supportive care....Omega three fatty acids, low dose aspirin therapy,enalapril, superoxide dimutase and other free radical scavengers may be indicated in some individual cases.* Thromboembolism "throwing a clot" is not uncommon in these patients and is why low dose (1/4 a baby aspirin once daily) may be recommended.* Liver disease often shows up as severe jaundice along with weight loss,vomiting and inappetence. These cases seem to have a better prognosis than those primarily affecting the kidneys and have shown good response to colchicine therapy with survival times over four years possible.

OTHER CAUSES OF KIDNEY FAILURE IN SHAR-PEI
(or ...Why you need to get the biopsy/necropsy specimens).* Glomerulonephritis* Pyelonephritis* Renal infarcts

YOU CANNOT ASSUME THAT EVERY SHAR-PEI THAT DIED OF KIDNEY FAILURE HAD AMYLOIDOSIS.
It is, however, the overwhelming cause of premature death in the breed.

Linda J. M. Tintle, D.V.M. Wurtsboro Veterinary Clinic, P.C. 251 Sullivan Street PO Box 910 Wurtsboro, New York 12790