Familial Shar-Pei Fever
Familial Shar-Pei Fever (FSF) is a hereditary inflammatory disorder seen in Shar-Pei. It
appears to be inherited as an autosomal recessive condition.
Clinical signs: Episodic fever is the most important and consistent clinical sign of this
disorder. The temperature commonly is in the 104-107°F (40°C-41.7°C) range. The
fever is generally self-limiting lasting 12-36 hours. Another common clinical sign often
accompanying the fever is swelling of a joint, usually the hock (tibiotarsal) joint and is
known as Swollen Hock Syndrome (SHS). This painful, hot swelling can also involve
the carpus (wrist) and the lips and/or muzzle. Dogs with FSF are sick -- they are
reluctant to move and when they do walk they have a characteristic "walking on eggs"
gait. They often are painful in the abdomen and have a characteristic "roached" back.
There can be gastrointestinal signs such as mild vomiting and diarrhea as well. These
signs are related to synovitis of the affected joint(s), pleuritis and/or peritonitis
(inflammation of the lining of the thoracic/abdominal cavity) and the accompanying pain.
Along with these clinical signs they are also not eating or drinking.
Pathogenesis: What we do know about this disease is as follows:
- The major function of the immune system is to recognize "SELF" and "NONSELF"
and then react appropriately to eliminate the "NON-SELF" antigens.
There are two arms of the immune system - INNATE IMMUNITY and
ADAPTIVE (HUMORAL) IMMUNITY. The innate immune system is set up to
react quickly by generating an inflammatory response. This is initiated by a
group of proteins known as PAMPs or Pathogen-Associated Molecular Pattern
proteins. The innate immune system is pre-programmed to a respond to a wide
variety of environmental triggers. The adaptive immune system is slower in onset
and has the advantage that it "remembers" previous encounters. Hence it "learns"
and reacts quicker and stronger in future episodes. Both these legs work together
to lessen the impact of bacteria, foreign material, viruses, fungi, tumor cells, etc.
on the body.
- Inflammation is a normal response in the body and is finely controlled by a
"checks and balances" system which regulates the duration and intensity of the
response. There are systems in place which turn "ON" the system and turn
"OFF" the system to maintain balance.
- A genetic defect in the innate immune system can lead to uncontrolled
inflammation resulting in AUTOINFLAMMAORY disease - a syndrome of
continuous (constant "ON") inflammation which is not healthy. A genetic defect
in the adaptive immune system leads to an over-reactive immune response
resulting in AUTOIMMUNE disease (the body reacting to itself).
- FSF is classified as an AUTOINFLAMMATORY DISORDER due to a genetic
mutation in innate immunity and may be the first such described disorder in dogs.
There are a number of autoinflammatory diseases described in humans such as
Familial Mediterranean Fever, Tumor necrosis factor Receptor - Associated
Periodic Syndrome (TRAPS), Cryopyrin - Associated Periodic Syndrome
(CAPS) and others. These are lumped together into Hereditary Recurrent Fever
Syndromes (HRFS). These are all diseases which are due to mutations in the
genes which regulate the production of inflammatory cytokines (chemical
messengers) such as those in the interleukin family. FSF dogs are in a constant
state of inflammation with high levels of inflammatory proteins such as IL-6, IL-
1β, acute phase reactant proteins, and serum amyloid A (SAA) protein, among
others. The development of systemic reactive amyloidosis is a potential
complication of all the autoinflammatory diseases.
- FSF is more complicated in Shar-Pei due to a genetic mutation which results in
Hereditary Cutaneous Hyaluranosis (HCH) - grossly seen as the excessive
wrinkles which define the breed. The genetic defect results in over-production of
hyaluronan (mucin). Low-molecular weight break down products of hyaluronan
metabolism are pro-inflammatory and exacerbate the pro-inflammatory process
involved in FSF. Hyaluronan is a normal substance in the body making up the
intercellular matrix or scaffolding between cells. Based on its cellular and water
content it can present as a free flowing gelatinous material to something as firm as
cartilage. Recently a mutation upstream of the HAS2 gene on chromosome13 has
been discovered. The mutation is known as the "meatmouth" mutation and is a
count number variation (CNV) consisting of multiple copies of a regulatory gene
controlling hyaluronan synthesis. Increased levels of hyaluronan are associated
with a tendency to develop FSF and amyloidosis. Research is continuing to focus
on this mutation in the hope of developing a blood test to determine an
individual's risk of developing FSF +/- amyloidosis.
- The tendency to develop amyloidosis may also represent an additional defect that
is probably present throughout the canine genome in all breeds of dogs.
Amyloidosis develops in the presence of chronic inflammatory diseases such as
heartworm, tuberculosis, systemic fungal diseases, chronic bacterial infections
and cancer. FSF and hyaluronosis are built-in triggers for the development of
amyloidosis and account for the increased susceptibility of the breed to this
complication.
- Pedigree studies indicate that FSF is an inherited disorder in the Shar-Pei
probably as an autosomal recessive trait. Survey results have indicated that as
many as 23% of Shar-Pei experience fevers of unknown origin. Shar-Pei with
FSF have increased levels of the cytokine Interleukin-6 (IL-6). IL-6 is involved
with the fever response and is an integral part of triggering the production of
Acute Phase Reactant Proteins by the liver. IL-6 is also involved in the Systemic
Inflammatory Response Syndrome (SIRS). Dysregulation of IL-6 is the cause of
much of the disease in Shar-Pei with FSF. IL-6 also plays a major role in the
body's stress response and serves to "prime" the immune system.
- Shar-Pei with FSF are at risk from early death from systemic amyloidosis. About
5% of the FSF dogs will develop renal failure including renal amyloidosis -- a
smaller percentage will develop hepatic amyloidosis. This is usually seen in
Shar-Pei between the ages of 2-5 years of age. They also seem more susceptible
to immune-mediated kidney disease such as membranous glomerulonephritis,
protein-losing glomerulopathies, DIC, thromboembolic phenomena such as
mesenteric, splenic and pulmonary embolism and Streptococcal Toxic Shock
Syndrome (STSS).
- Early on, FSF in Shar-Pei was hypothesized to be an animal model for Familial
Mediterranean Fever in humans. Recent work indicates this is not true, although
FSF is very similar to FMF in man.
Laboratory Findings: Unfortunately there are no blood tests, etc. which are specific for
FSF. During a fever episode there will often be an increased white blood cell count, an
increase in liver enzyme levels and other non-specific findings. Work done by Dr. Gary
Johnson at the University Of Missouri College Of Veterinary Medicine to develop a
DNA blood test to screen for the disease was unsuccessful. The research effort will still
continue.
Treatment: It is very important to monitor the temperature in this condition. Initially,
fever can be treated using aspirin. Usually a regular strength adult aspirin (325mg) is
given every 6- 12 hours for the first 24 hours and then twice a day for 3-5 days thereafter.
It is important to continue treatment for several days flowing resolution of the episode to
prevent rebound fever. In rare cases where aspirin doesn't work or for extremely high
fevers, dipyrone is given. Other NSAIDs may also be used but response may be a little
unpredictable. Some patients will require supportive care with intravenous fluid therapy
and in extreme cases emergency treatment similar to heat stroke treatment. Antibiotics
are not normally indicated in this condition.
Colchicine: Colchicine is a drug that has been in use in people with FMF to prevent
amyloidosis. It is currently being recommended in Shar-Pei with FSF for the same
purpose. No studies have been completed to determine if it is useful for this purpose in
the Shar-Pei or not. The clinical impression is that it does help. Those dogs on
colchicine seem to have fewer FSF episodes and less severe signs while on the drug.
Side-effects appear to be minimal at this time. I currently recommend stopping
colchicine therapy during an FSF episode while aspirin or other NSAIDs are being used
as there is increased risk of gastritis.
Prevention: Shar-Pei with FSF only show symptoms sporadically. It would appear that
there are "triggers" involved in initiation of the FSF episodes. One of the major triggers
appears to be stress. This may be a dog training class, a dog show, another illness, a dog
in heat, excessive exercise, etc. If the owner can recognize these triggers and take steps
to avoid them the number of FSF episodes can often be reduced. Diet does not appear to
be helpful in prevention of FSF or kidney disease. Surely diet has a role in the
management of kidney disease once clinical signs are apparent. Low dose aspirin therapy
may be useful in decreasing the incidence of FSF and its severity as well. Aspirin may
also be useful as an adjunct therapy in the prevention of thromboembolism.
Monitoring: Monitoring for the complications which often accompany FSF is one of the
major goals for the owner of an FSF dog. The primary and most consistent
sequela to FSF is kidney failure either due to immune-mediated kidney disease or renal
amyloidosis. I currently recommend monitoring a urinalysis every 3 months. The
sample should be collected first thing in the morning after the water has been taken up
overnight. I primarily look at the urine specific gravity which is a measure of the
concentration of the urine and the protein levels in the urine. When the kidneys begin to
fail the initial indication is a loss in the ability to produce a concentrated urine. This
occurs before there are blood changes related to kidney failure. Increased water
consumption, increased urination are the clinical signs associated with a loss of
concentrating ability, but these signs are often not recognized. I also think it is wise to do
a blood panel every 6-12 months and certainly do one if the urinalysis is abnormal.
Weighing your dog periodically is very important. We often don't recognize a significant
weight loss because it is very subtle over a longer period of time. Water consumption
and appetite are other important indicators to watch. Amyloidosis is usually medullary in
Shar-Pei but can manifest as a protein-losing nephropathy and UPC ratios and treatment
with ACE -inhibitors may be necessary.
Complications of FSF: We have already discussed the kidney complications in this
condition. Other complications which have been documented include thromboembolism
(mesenteric, splenic, pulmonary), DIC (disseminated intravascular coagulation), SIRS
(systemic inflammatory response syndrome), MODS (multiple organ dysfunction
syndrome), STSS (streptococcal toxic shock syndrome), hypertension associated with
renal failure. Many of the deaths following an acute FSF episode are due to these
complications. No FSF episode should be treated lightly!
Diagnosis: There is no specific diagnostic test for FSF at this time. Diagnosis is based
on the clinical sign of episodic fever in a Shar-Pei. I think every Shar-Pei that dies
should be autopsied to determine the cause of death, but this is even more critical in cases
involving FSF. Renal amyloidosis can only be diagnosed based on kidney biopsy and
staining with Congo Red stain. This stain is specific for the presence of amyloid.
Amyloid has been found in other tissues in Shar-Pei as well so special staining should be
requested on all tissues submitted for histopathology. Many dogs with FSF will not have
amyloid in the tissues at the time the tissues were harvested -- this means the absence of
amyloid in a biopsy specimen does not mean that dog will not or would not have gone on
to develop amyloidosis at a later time. To further confuse the issue, not all Shar-Pei with
amyloidosis have shown signs of FSF.
Future: Research is currently underway at the University Of Missouri College Of
Veterinary Medicine by Dr. Gary Johnson to develop a DNA blood test. The gene for
human FMF was sequenced in the fall of 1997 and with that information Dr. Johnson had
hoped to sequence the FSF gene. That information was applied by Dr. Gary Johnson to
FSF in a research project founded by the CSPCA Charitable Trust. That project did
determine that the mutations causing FMF in man do not exist in FSF in the Shar-Pei;
hence they are two distinct, although similar diseases. There are other hereditary
inflammatory fever disorders in man and Dr. Kastner at the National Institutes of Health
are looking at the disorder with information supplied by Dr. Tintle. Familial Hibernian
Fever in man has also been ruled out as the cause of FSF by Dr. Johnson with
information supplied by NIH. Work will continue to find the genetic mutation(s)
responsible for FSF in Shar-Pei.
As of this writing the mutation responsible for FSF has not been found. If a test can be
developed, a screening program can be established to screen breeding stock and
determine normal individuals, carriers and affected dogs. With this information Shar-Pei
breeders can gradually eliminate this genetic disease from the breed. One of the major
obstacles to the research revolves around the unpredictable phenotype of FSF. There is
no consistent age range when clinical signs develop, the clinical signs can be variable,
some dogs develop amyloidosis, some don't, etc. This makes it very difficult to use
genetic selection methods which are based on phenotype.
Recommendations: All Shar-Pei with FSF should be on colchicine and be regularly
monitored via urine samples and blood work for development of complications. Dogs
with FSF should not be used in breeding programs and should be neutered. Dogs with a
family history of FSF should be on colchicine and monitored. Dogs with FSF should be
maintained as stress-free as possible.
(6/09/09)
(Fig 1.)
Fig.1 shows swelling of the left hock. The hock is erythematosus and very painful. This
is known as Swollen Hock Syndrome (SHS) in Shar-Pei circles. This term should only
be used in dogs with the fever characteristic for FSF. Other causes of a swollen hock
without fever are mucin accumulation ("socks"), allergic reaction, and cellulitis.
(Fig 2.)
Fig 2.shows the characteristic stance of these dogs.
Typical fever associated with FSF
(Fig 3.)
This figure illustrates that in less common cases the
carpus is affected and rarely there can also be a swollen, painful lip or muzzle.
(Fig. 4)
This figure illustrates a kidney affected by amyloidosis.
- Rivas AL, Tintle L, et al: A canine febrile disorder associated with elevated interleukin-6,
Clinical Immunol Immunopathol 64:36-45, 1992.
- Tintle, L: Familial Shar-Pei fever and familial amyloidosis of Chinese Shar-Pei dogs:
http://www.royalsharpei.com/amyloidosis.htm
- DiBartola SP, et al: Familial renal amyloidosis in Chinese Shar-Pei dogs, J Am Vet Med Assoc
204:1212-1216, 1994.
- Olsson M, Meadows JRS, Truve K, Rosengren Pielberg G, Puppo F, et al. (2011) A Novel
Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a
Periodic Fever Syndrome in Chinese Shar-Pei Dogs. PLoS Genet 7(3): e1001332.
doi:10.1371/journal.pgen.1001332
© Jeff Vidt, DVM (12/2/12)
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