Familial Shar-Pei Fever and Familial Amyloidosis

of Chinese Shar-Pei Dogs

Linda J.M. Tintle, D.V.M.

Shar-Pei with Familial Shar-Pei Fever (FSF):

 * Have one or more bouts of unexplained fever, usually 103-107 degrees F (39.4-41.7 degrees C) but rare cases may go higher.

* If they do not 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.

* One or more of the following signs may accompany fever episodes:

                * 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 tibiotarsal or hock joint (SHS).

                * Sometimes a swollen painful muzzle.

                * Abdominal pain, reluctance to move, "roached" back, mild vomiting or diarrhea, shallow rapid breathing.

Familial Mediterranean Fever (FMF) vs. FSF - FMF is:

* An autosomally recessive inherited periodic fever disorder of humans. The hereditary fever syndromes are inherited disorders characterized by self-limited episodes of fever with inflammation of joint or body cavity linings without any apparent infectious cause.

* 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 ankles or top of the foot.

* Free from symptoms between attacks.

* May develop amyloidosis.

Shar-Pei with FSF have abnormally high resting levels of a cytokine 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 cytokines, for the production of the acute phase reactant proteins (APP) of inflammation... the precursors of Amyloid AA. Chronically elevated levels of IL-6 and other cytokines lead 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 cannot be broken down normally by the animal because of a defect in metabolism 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 the disease.  Amyloid 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.

FSF is an autoinflammatory disease characterized by dysregulation of the normal paths of inflammation.

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 Scarlett, CP van Tassel, & FW 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. There is evidence that environmental influences are also important in whether or not an at-risk individual develops amyloidosis.

* Private communication with many of the original breeders and importers of these dogs has led me to believe that many of these imported foundation dogs were affected by this immune system dysregulation.  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.
• Fever episodes should be considered to be an important marker that the dog is at extremely high risk to develop amyloidosis and should be carefully monitored BUT not all FSF patients will develop amyloidosis.

Amyloidosis>>> kidney failure or, less commonly, liver disease/ failure.

Amyloidosis is a killer.

* Deaths have been reported to me as young as 8 months of age and as old as 12 years of age.  It most commonly strikes between 3 and 5 years of age.

* Amyloidosis can only be diagnosed by surgical biopsy or by 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.  I believe the incidence may be higher now.

How is FSF diagnosed?

* No single test is yet available

* Still a clinical diagnosis by history, signs and excluding the other possibilities.

* Blood tests are usually negative/normal except that an elevated white blood count with a left shift is not uncommon as is mildly elevated alkaline phosphatase levels.

I perform the following minimum database on patients with possible FSF and then at least annually thereafter:

* Complete blood count (CBC) with differential, serum chemistry panel, and complete urinalysis (UA) on a first morning urine sample.

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.  Do not forget to consider Leptospirosis where endemic.

* 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 affected Shar-Pei have medullary amyloid and may or may not have proteinuria (unlike humans) but proteinuria is always a significant finding.  Loss of ability to concentrate urine (specific gravity consistently 1.010 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.

Treatment of FSF episodes.

* Tender loving care, close observation of body temperature and otherwise benign neglect.

* Buffered aspirin, Metacam (metacarpfen) - Canadian S-P owners have reported that this has worked very well in reducing fever and I am starting to recommend having it on hand to my clients' whose dogs experience episodes of fever now that it is available in the U.S.

* 1.0 ml of 50% Dipyrone SQ, or Banamine (flunixin meglumine) to reduce fever and provide pain relief, particularly for fevers > 105 degrees.

* Extremely high fevers or other 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 and 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 vast sloughing of skin have been reported to or seen by Dr Jeff Vidt and I.  These seem to resemble the "flesh eating" Streptococcus infections reported in humans (although other bacteria have been cultured as well) and require aggressive antibiotic and supportive treatment.  These can be fatal even with treatment.  A recent reports suggest that this is an immune mediated vasculitis and steroids +/- azathioprine may be indicated.