An Article by Linda Tintle, DVM
Published in the July/August 1993 issue of The Barker
What is Amyloidosis?
A generic term for a collection of diseases that result in the abnormal deposition of amyloid protein throughout the body.
How is Amyloid Made?
When inflammation occurs, certain chemicals are produced and released into the blood. These chemicals of inflammation are called the Acute Phase Reactant Proteins (APP). After the inflammation has gone away, the APP are broken down by the body and excreted. Dogs (or people) with amyloidosis can't break these APP down into excretable form and instead turn it into Amyloid AA and dump it outside the cells but still within the body.
Why does the Amyloid make them sick?
Amyloid is constantly deposited outside the cells. It builds up like a garbage heap in an alley vay until it starts to squeeze the adjacent cell walls.
The compressed cells can't work properly. The damage or disease that results depends on what kinds of body cells are most severely damaged or killed.
Kidncys can't heal themselves by growing new kidney cells. If a kidney cell dies, it is gone for good and can't be replaced. This is why the amyloid protein usually causes kidney failure first.
tress commonly, the liver fails from amyloidosis.
What is FamiLiial Shar-Pei Fever (FSF)?
l Gave one or more bouts of unexplained fever, usually 103-107 degrees but rare cases may go h igher.
Fevers usually start when they are 18 months old but sometimes first attack is not until they are full grown. Fever episodes usually become less frequent with age.
Fevers last 24-36 hours in most cases without treatment.
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 ("synovitis"). One or more joints may be affected but most cases involve the tibiotarsal or "hock" joint... Swollen Hock Syndrome (SHS).
Sometimes a swollen, painful muzzle.
Abdominal pain, reluctance to move, "roached" back, mild vomiting or diarrhea, shallow rapid breathing.
Swollen hock syndrome was reported to be experienced by up to 53% of those dogs having fever episodes by owners responding to the 1991 National Specialty survey.
What is Familial Mediterranean Fever and What does FSF have in Common with FMF?
An inherited disorder of humans, reportedly as an autosomally recessive trait.
Recurrent bouts of [ever, usually starting in childllood.
Polyserositis, involving one or more of the following:
2. Chest pain.
3. Joint pain, usually involving one of the larger joints.
4. Swelling/inflammation of skin about the ankle or top of foot.
5. Free from symptoms between attacks.
6. May develop amyloidosis.
Before colchicine therapy, up to 30% of FMF patients died of amyloidosis.
FMF is accepted to be a disorder of the regulation of the immune system, specific defect unknown.
What Causes the Fevers in FSF?
We don't know exactly.
What we Do Know: Shar-Pei seem to have a problem regulating their immune system. The immune system:
Recognizes "self" from "non-self' and eliminates foreign invaders such as bacteria and removes cancer cells.
It does this with specialized cells and/or their chemical products.
It is miraculaously complex but is controlled in part by a vast communocation system involving chemical messengers called CYTOKINES.
Shar-Pei with FSF have abnormally high levels of a cytokine called Interleukin-6.
Interleukin-6 (IL-6) "turns on" various parts of the immune system. It is involved in contl-ol-ling the fever response and is a trigger, alone or with other cytokines, for the production of the APP... the precursors of Amyloid AA.
Shar-Pei with FSF:
Have excessively high levels of certain protective antibodies (immunoglobulins).
Have an exaggerated rate of division of their Iymphocytes... one of the immune system cells rcspollsilgle for fighting infection and mounting an antibody response...when grown in the laboratory and compared to normal dogs.
Why do some dogs with FSF get Amyloidosis and others don't?
Shar-Pei with FSF have an abnormal inflammatory response... the immune system's accelerator pedal, IL-6, is always being pushed, sometimgs a little, sometimes a lot and this probably varies with individuals.
Extra APP are produced chronically.
Some Shar-Pei can't properly excrete the APP and dump them within the body as amyloid.
In people with FMF, the fever disorder and the abnormal production of amyloid protein are believed to be different parts of the same or linked genes.
Patterns of Inheritance
we have submitted a paper which has been accepted by theJorunal of Heredity offering evidence that this disorder is inherited as an autosomally recessive gene. It will be published in late 1993.
Based on extensive pedigree analysis going back to originally imported foundation stock...
Heterozygous carriers, having one normal gene and one abnormal gene for the disorder, do not develop amyloidosis.
Only when doubled up on the abnormal gene... homozygous...do they deposit amyloid.
Normal X Carrier
Carrier X Carrier
Carrier X Amyloid-Affected
Heterozygous Carriers May:
Experience the effects of abnormal immune system regulation including episodic fevers +/- Swollen Hock Syndrome .
May never experience a fever and be asymptomatic, silent carriers.
Have an increased risk for thromboembolic disease ("strokes" and abnormal blood clots causing disease or very rarely, sudden death).
Possibly have an increased risk for early death from certain cancers.
Live out relatively normal lifespans (eight years) without ever developing amyloidosis.
IL-6 has been shown to be a growth factor for malignant plasma cells (plasmacytomas and myelomas) and because IL-6 "turns on" the development of many cell types, it is not unlikely that it may "turn on" abnormal or malignant cell lines as well. This could explain the un- usual number of cancer cases in patients with FSF. I am looking into a study of this with veterinary cancer specialists.
Less commonly, signs of amyloidosis may precede outbreaks of fever or the patient may never experience or report any fever spisodes. This is called "Phenotype II" in FMF.
Deaths from amyloidosis have been reported to me as young as eight months of age and as old as 12 y ears.
Most die between three and five years of age.
Most Common Signs of Advanced Amyloidosis...
Unexplained Weight loss.
Increased thirst and frequency of urination.
"Bad breath" as a result of uremia or the build-up of toxins/wastes in the bloodstream as the kidney +/or liver fails to process them. How is Amyloidosis Diagnosed?
Amyloidosis can only be diagnosed by examining specially stained tissue samples microscopi-cally ull(ler polarized light.
Tissues must be obtained by surgical biopsy or, after death, by necropsy. The veterinarian sublllittillg the sample requests that it be stained with "Congo Red" to detect the presence of amyloid .
Dr. Quimby and his graduate students are working on a blood test involving monoclorlal antibodies of serum amyloid A but this is in the early investigational stages.
How common is amyloidosis in Shar-Pei?
The precise incidence of amyloidosis in Shar-Pei is impossible to determine at this time. Survey Results 1991 National Specialty...23% w/fever of unknown origin. Even if everyone who did NOT return their survey had NO fevers...we would still have...ll+%. That's still a lot of dogs experienceing fever episodes. Private communication with some of the original breeders and importers of the foundation stock of our dogs has led me to believe that many of them were affected by the immune system dysregulation.
How is FSF Diagnosed?
No single test available.
Still a diagnosis of excluding the other possibilities.
Blood tests and cultures are usually negative/normal except elevated WBC with left shift is not uncommon.
What's All This About an IL-6 Test?
Dr. Ariel Rivas is working at the Diagnostic Laboratory of the New York State College of Veterinary Medicine at Cornell University to develop a blood test to measure IL-6 levels of dogs.
Because Shar-Pei with FSF have elevated levels of IL-6, we are hoping to use this as a screen-ing test for this disorder.
Before this, IL-6 levels could only be measured by growing special cell lines in tissue culture media...an elaborately expensive, time consuming and very complicated method.
Questions About The Test...
How old do they have to be to be tested?
How specific is it for this disorder?
Will it tell me if my dog will die from amyloidosis?
Will it be expensive?
How is FSF Treated?
Fever episodes are treated with anti-inflammatory medications, e.g. Dipyrone.
Extremely high fevers may require more aggressive treatment, similar to that of "heat stroke."
Experimental...use of the drug needs to be reviewed and treated cases compared to untreated cases before it can be widely accepted.
Used in FMF to reduce the severity and frequency of fever outbreaks and to block the development of amyloidosielil art rcsults in Shar-Pei ssrith FSF are encouraging.
How is Amyloidosis Treated?
Most patients don't show signs until disease is well-advanced and they are dying. Treatment is difficult if not impossible in most cases.
Treatment of advanced kidney and liver failure needs to be designed to fit the needs of each individual patient and should be left to your veterinarian or specialist she/he refers you to.
We have used colchicine along with more conventional therapies in somc, less advanced cases. Sorne arc still alive two years post-diagnosis. These are the EXCEPTIONS not the rule. More on Treatment and Diagnosis of Amyloidosis...
Dr. Jeff Vidt wrote an excellent article: "Plan of Action for Amyloidosis" in Nov/Dec 1992 issue of The Barker on signs to watch for and treatment of amyloidosis which covers the subject in depth.
I have a treatment protocol for FSF/amyloidosis that I will send to any veterinarian on request.
Does Every Shar-Pei that Dies of Kidney Failure Have Amyloidosis?
Lots of causes of kidney failure and some are related to FSF and some not.
Amyloidosis does, however, seem to be the OVERWHELMING cause of premature death from kidney failure in Shar-Pei but only histopathologic exam (biopsy or necropsy) will tell you for sure.
Shar-Pei with FSF may also develop membranous glomerulonephritis with or without amyloidosis as a result of immune complex deposition. Glomerulonephritis is common in imune-medicated diseases.
Glomemlonephritis forms as a result of the deposition of immune complexes along the glomerular capillary wall and ultimately results in the destruction of the glomeruli within the kidney, loss of protein in the urine and kidney failure.
Other related kidney disease...
Pyelonephritis (infection of the kidney) may occur commonly in FSF/amyloidosis patients.
They can also throw a clot to their kidneys...an "infarct."
These conditions may cause or contribute to kidney failure and are non-amyloid related kidney disease that may be triggered because of their immune system problems for FSF.
A Shar-Pei may die of kidney failure at an early age and be negative for amyloid.
The dog's kidney failure may OR MAY NOT have been related to FSF and at this time. It is impossible to determine any relationship with certainty.
These animals can only be classed as suspicious, unknown.
Currently available diagnostic tests
I recommend a minimum database of CBC with differential, semen chemistry panel, urinaly-sis and urine protein/creatinine ratio for my patients with FSF if the owner is willing. Lyme disease (Borreliosis) should be ruled out in endemic areas.
Immune panels, Immunoglobulin levels, cultures, radiographs and joint taps are sometimes needed .
Can I use urine protein levels to screen my dogs?
Most non-Shar-Pei that develop amyloidosis get a glomerular amyloidosis after nine years of age They spill a lot of protein in their urine.
Humans with FMF and amyloidosis spill a lot of protein in their urine.
Unfortunately, Shar-Pei (and Abyssinian cats with Familial Amyloidosis) most commonly get medullary amyloidosis and they may or may not spill protein in their urine. This makes the test worthwhile (because a positive may be significant and should be followed up with a urine pro-tein/creatinine ratio) but a negative doesn't mean you are safe. Dr. Linda Tintle, 251 Sullivan Street, P.O. Box 906, Wurtsboro, New York 12790. (914) 888-4884.
Skin problems are not due to the wrinkles! No special care should be necessary between the folds. Skin problems in the breed are most commonly caused by hypothyroidism (low thyroid), a depressed autoimmune system, or allergies.
This is a condition where the eye-lashes come in contact with the surface of the eye. As puppies 3-6 weeks old, tacking can be done to "train" the eye-lashes in the right direction. This should not be done by default. This procedure may be repeated a couple of times, but if tacking ultimately fails to correct the problem, entropion surgery may be necessary.