Hyaluronosis, Familial Shar-Pei Fever and Amyloidosis

posted: by: Linda J.M. Tintle DVM Tags: "Clinic Specials" "News" 

Hereditary Cutaneous Hyaluronosis (HCH):  Shar-Pei over-express Hyaluronan Synthase 2 (HAS2).  Excess hyaluronan (HA) leads to their unique skin thickening and wrinkles because of a regulatory mutation.  The mutation is a duplication that occurs in multiple copies.  Individual Shar-Pei dogs vary in the number of copies of this mutation from dog to dog.  The mutation is a copy number variant or “CNV”.

Excess hyaluronan (the main component of “mucin”) may form vesicles or bubbles in the fragile skin.  Hyaluronan health is integral to Shar-Pei health.  Damaged or degraded low molecular weight hyaluronan is a “damage associated molecular pattern” (DAMP), a danger signal that can activate the innate immune system.  Native high molecular weight HA is health promoting and healing.  You may improve Shar-Pei health by preventing or offsetting damage to their abundant HA.

Familial Shar-Pei Fever (FSF) is a periodic fever syndrome that is characterized by random inflammatory events with high fever, sometimes with swelling about joint/s or muzzle, that usually last 12-36 hrs.  FSF is an autoinflammatory syndrome (not autoimmune).

Their underlying genetic defect is an unstable duplication in a regulatory gene upstream of Hyaluronan Synthase 2 (HAS2) that is described as the “meatmouth” mutation in our March 2011 article published in PLoS Genetics.  Original, traditional-type Shar-Pei with less padded muzzles, less skin thickening and wrinkling have a slightly different mutation (“traditional”) in this same location.  The “meathmouth” mutation appears to predispose Shar-Pei (and some Shar-Pei mixed breeds) to inappropriate inflammatory responses.  This may result in chronic elevations of inflammatory chemical messengers in the bloodstream.  Shar-Pei may have abnormal initiation and also amplification of inflammation as a result of this genetic copy number variant (CNV) mutation.  They may over-react to infection and damage.  The greater the number of copies of the mutation present in the dog, the more reactive inflammation may result when HAS2 is up-regulated.  Hyaluronan is also degraded and turned over rapidly: in hours, days, or weeks depending on its location.  The breakdown of HA into fragments for elimination may also contribute to autoinflammation.

A copy number variation (CNV) is when the number of copies of a particular gene varies from one individual to the next.  A gene is a unit of heredity on a DNA sequence.

Shar-Pei have a CNV of a mutated gene near the one encoding hyaluronan synthase 2 (HAS2, an enzyme that makes hyaluronan) on canine chromosome 13. This mutation may be either the "traditional" mutation common in the original traditional bonemouth-type dogs or the "meatmouth" mutation that occurs in the western-style, more heavily wrinkled and padded Shar-Pei dogs. The increased CNV causes over-expression of HAS2 and increased amounts of hyaluronan produced around cells. Increased copies of the mutated gene lead to abnormal excess hyaluronan. The CNV varies between individual Shar-Pei. All Shar-Pei carry at least two copies of the mutated gene. Some Shar-Pei have many more copies of the mutated gene than other Shar-Pei. Increased numbers of mutated copies (high CNV) has been linked to increased risk for Familial Shar-Pei Fever (FSF) and amyloidosis.  Shar-Pei mixed breeds may experience FSF through inheritance of this mutation.

Low molecular weight fragments of hyaluronan both activate and prime the inflammasome leading to the release of IL-1beta and then IL-6, two major drivers of fever and inflammation.  Mutations leading to aberrant inflammasome function have been associated with the human autoinflammatory syndromes Familial Mediterranean Fever (FMF), TRAPS, CAPS and gout.

Shar-Pei with Familial Shar-Pei Fever (FSF) may show the following signs:
  • 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.  Fever greater than 106 degrees is a medical emergency and owners should seek veterinary treatment for the hyperthermia.
  • Without fever, it is NOT “classic” FSF. (Assuming not on colchicine & supplements).
  • 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.  It is possible for the fever events to be brief, lasting only a few hours.
One or more of the following signs may accompany fever episodes:
  • Swelling around a joint with or without inflammation of the joint itself. One or more joints may be affected but most cases involve the tibiotarsal or hock joint (swollen hock syndrome). Of the dogs that had experienced periodic fever episodes, approximately 53% had experienced swollen hock/s at some time along with the fever when owners at the CSPCA National Specialty were surveyed in 1994.  Be careful not to mistake the normal "socks" (excess wrinkling around the hocks) on some individual Shar-Pei for the acute swelling that occurs surrounding the hock during or around the time of a fever episode.
  • Sometimes a swollen painful muzzle.
  • Abdominal pain, reluctance to move, "roached" back, mild vomiting or diarrhea, shallow rapid breathing. The proinflammatory cascade give the dogs flu-like symptoms and similar discomfort.
  • CBC blood test will usually show neutrophilia (although neutropenia may occur early in the course), and often monocytosis due to activation of neutrophil and monocyte chemotaxis.  Shar-Pei with FSF may have elevated alkaline phosphatase, hypercholesterolemia, hypomagnesemia, hyperglobulinemia and slight elevations in total bilirubin on blood chemistry panel.
Amyloidosis is a disease caused by abnormal deposition of the breakdown products of chronic inflammation in the extracellular matrix (between cells).  The severity of disease and risk for amyloidosis will vary with the amount of inflammation initiated and the autoinflammatory over-reaction.  The chronic background inflammation puts affected dogs at risk for developing reactive systemic amyloidosis which can lead to early death from kidney failure.

Not every dog with FSF will develop amyloidosis but the fevers are a warning sign that they have aberrant autoinflammation and are at high risk for kidney disease.  Shar-Pei with FSF can live to over 10 yrs of age.  Two of my mother’s Shar-Pei lived to 12 ½ and 15 ½ years respectively with lifelong FSF and this is not uncommon in my patients.  By doing everything you can to reduce their chronic inflammation and monitor their disease, you can help them live their best possible lives - however long that may be.  Unfortunately, a combination of genetic predisposition (increased CNV) and environmental influences may lead to early death from kidney or, more rarely, liver failure due to amyloidosis in some individuals.

The diagnosis of Shar-Pei Fever is made after ruling out other causes of fever with diagnostic tests indicated by the dog’s condition but a minimum baseline of first morning urinalysis, CBC, chemistry profile, T4, +/- panel for tick-borne diseases is common.  Other tests, including those for autoimmune disorders, may be needed.  It is a diagnosis by exclusion at this time.  I am collaborating with Dr. Kerstin Lindblad-Toh and Mia Olsson on a genetic test using the CNV mutation that is currently in development and undergoing validation studies at the Broad Institute of MIT and Harvard and Uppsala University in Sweden.  A commercial test that is accurate, meaningful and useful to veterinarians, Shar-Pei owners, and breeders is the goal of the on-going study.

Because fever events are a marker for the presence of autoinflammatory disease, therapy should be started early to prevent complications.  Some dogs have only one observed fever event yet die prematurely from amyloidosis – the number and frequency of fever events does not correlate with the severity of underlying chronic inflammation.  In rare instances, dogs may die of amyloidosis without any observed fever events or may have their first fever after going into kidney failure.

My current treatment recommendations for Shar-Pei Fever include 0.025-0.03 mg/kg of colchicine twice daily or less to bowel tolerance.  I recommend that the dog be started on a low dose once daily and then gradually increased to the maximum recommended amount (up to the calculated dose above) as tolerated without diarrhea once or twice daily.  For most average weight Shar-Pei, this is one 0.6 mg tablet given twice daily.  Colchicine is a potent drug but it accumulates in white blood cells (the desired target for treatment) and GI signs occur long before other serious side-effects.

I have never seen evidence of any damage from colchicine except for a transient, treatable diarrhea that goes away when the drug is withdrawn in sensitive patients.  Colchicine treats the underlying pathology by blocking the movement of neutrophils (one of the white blood cells), decreasing levels of cytokines (the messengers of inflammation), interfering with mast cell degranulation and blocking the formation of amyloid protein (a waste by-product of inflammation).  In humans, it has proven to be safe in infants, pregnant women and when given lifelong.  Treatment is for life.  I have been using the drug since 1993 and have had individual patients on the drug safely for over 10 yrs.  Some dogs cannot tolerate colchicine without chronic diarrhea and they are given smaller amounts or none if it is severe.  Colchicine and cyclosporine (Atopica®) should not be given together because of increased risk of bone marrow suppression.

Currently, sale of colchicine has been restricted in the U.S.A. by the FDA to one manufacturer, URL Pharma, under the brand name "Colcrys®" with an exorbitant price increase. URL Pharma has instituted a Patient Assistance Program for Shar-Pei that is administered by NeedyMeds. There is an application for the program (income adjusted fee structure) on www.NeedyMeds.org website HERE.  Applicants must provide a valid Colcrys prescription from a licensed veterinarian, and must attest that Colcrys will be used solely for their Shar-Pei dog. Applicants who qualify for the program will be able to select a 30-day supply (60 tablets), 60-day supply (120 tablets) or 90-day supply (180 tablets) of Colcrys. Those receiving financial assistance must re-apply for the program annually. The prescribing veterinarian must complete and sign several portions of the application. Colchicine may also be prescribed and purchased legally through compounding pharmacists in tablets or flavored suspension and is available as a generic prescription drug in Canada and other countries.

I treat the fever events with 50% dipyrone (500mg/ml) injectable (usually 0.5-1.0 ml/dog under the skin), or meloxicam (Metacam®), a non-steroidal anti-inflammatory drug or NSAID (by weight per package insert instructions). Dipyrone is an IL-1 beta inhibitor that is available from compounding pharmacists as injectable or in oral suspension or may be purchased over-the-counter in many non-U.S. countries.  Aspirin has also been reported to be effective.  Some fevers are very serious and can require emergency veterinary treatment if they approach or exceed 106 degrees F (41° C).  Shar-Pei owners should discuss treatment of acute fever events with their veterinarian because treating the fever as early as possible in the inflammatory cascade can often stop it from becoming life-threatening and it is best to have medication available on-hand at home.  Avoid giving NSAIDs with corticosteroids like prednisone and your veterinarian should be alerted your dog is vomiting because gastric ulcers can be a common complication.

Use caution with ice packs or baths: external cooling efforts should be reserved only for those dogs with fevers approaching 106 degrees while en route to a veterinarian.  Unless the dog’s internal thermostat is reset with medication, the dog’s body will simply work harder to keep the fever up and may prolong the fever event.  An ice pack wrapped in a damp towel that is placed in the groin area will help cool the patient en route to emergency care.

Some fever events may be initiated by infection.  If the fever is severe, persistent and/or poorly responsive to anti-fever drugs like dipyrone, aspirin or NSAIDs, there may be an underlying infection that needs treatment.   Veterinary care should be sought whenever the fever is severe, worse than usual for that dog, lasts longer than 48 hrs or is not responding to anti-inflammatory medication.  In rare instances, a neutrophilic vasculitis and/or septic shock-like syndrome (STSS) with necrotic skin sloughing can occur.  The latter is often associated with bacterial hyaluronidases that break down the abundant mucin in Shar-Pei skin.  This can be life-threatening.

Your Shar-Pei should get regular and routine monitoring of first morning urine with urinalysis (UA) as well as a CBC, blood chemistry profile and T4.  Urine Specific Gravity at or below 1.020 is often the first sign of Shar-Pei kidney trouble and, if present, the UA should be repeated to see if the dog has a consistently low specific gravity.  Medullary amyloidosis is the most common kidney disorder in Shar-Pei and proteinuria is usually a late-stage event.  Urine protein levels should also be monitored and a urine protein to creatinine ratio performed if proteinuria is found on routine UA.   FSF patients should be examined and tests performed whenever they are not eating normally, if they are vomiting, having diarrhea for more than a few days, acting sick in any way or if they are just “not right”.  The bare minimum is annually in the healthy active young dog and many dogs should be checked more often.

In addition, Shar-Pei are prone to mast cell disease including mast cell tumors. The binding of HA to its receptor CD44 has been shown to play a critical role in regulation of murine cutaneous and connective tissue mast cell proliferation.  It appears that CD44-HA regulates resident cutaneous mast cell populations.  As the CD44-HA interaction may modulate local immune responses through regulation of mast cell functions, excessive HA and its subsequent damage and degradation may also play a role in the breed’s predilection for allergic skin disease and other mast cell driven inflammation.

Corticosteroids (for example medications like prednisone or dexamethasone) or cortisol produced by the dog’s body during stress (this may happen during a high fever or when ill) can shut down the production of hyaluronan by HAS2.  These steroids may shrink the Shar-Pei’s muzzle and they may lose wrinkles.  Very low dose prednisone is sometimes used for this reason to treat severe vesicular cutaneous hyaluronosis (bubbles of mucin in skin) or lymphedema of the hocks (chronic swelling due to fluid buildup).  A Shar-Pei that has a suddenly shrunken muzzle for no apparent reason should get a full physical exam and lab tests.

Addressing Hyaluronosis (the downside to Shar-Pei Wrinkles):

1.  Feed a High Quality diet low in simple carbohydrates: grain-free or containing small amounts of whole healthy fresh grains if possible.  Pasture-fed meat source is preferable if money is no object (grain-fed meat has a high ratio of omega 6 to omega 3 fats and is lower in antioxidants and conjugated linoleic acid).  The goal is to shift the arachidonic acid pathway away from pro-inflammatory end-products.  A high dietary omega 3 to omega 6 fatty acid ratio may help reduce inflammation and result in improved overall health (including decreased anxiety!).

2.  High dose omega 3 fatty acids from fish oil daily. Again, shift to anti-inflammatory end-products but also for its resolvins and other inflammation-resolving mechanisms at high doses. A high dietary omega 3 to omega 6 fatty acid ratio may help reduce inflammation and result in improved overall health including decreased anxiety.  (900-1800mg EPA, 450-900mg DHA/day – source is important to ensure no rancidity or contaminants http://shop.zonehealth.com/product/detail/101.aspx )

3.  Lecithin: 1-2 Tbl of granules (7.5 – 15 gms) per day in food.  To alter the phosphatidylcholine composition of the “hyaluronasome” in plasma membrane lipid rafts; may impact how HA fragments are internalized for further degradation. ( http://www.vitacost.com/NSI-Lecithin-Granules-Unflavored-15-grams-per-serving-32-oz or local vitamin & health food store).

4.  HyVitality®: a formulation of my recommended vitamins, minerals, antioxidants and phytochemicals that were chosen for their HA health promoting effects.  Magnesium is integral to stabilizing HA in its high molecular form and magnesium deficiency is a very common finding in the breed.  Severe cobalamin (Vitamin B12) deficiency is also common in Shar-Pei. This supplement was developed because it was difficult for clients to purchase the correct canine dosages using over-the-counter products designed for humans.  Working with a trusted manufacturer has allowed me to be assured of purity and quality: Made in U.S.A. in a cGMP facility.  (Average Shar-Pei dose contains 50-80mg Alpha Lipoic Acid, 60mg Coenzyme Q10, 80-160mg Magnesium from dimagnesium malate), 1000 mcg Methylcobalamin, 25mcg Vitamin K2 and a proprietary blend of Boswellia Serrata, Curcumin, Diosvein™ Diosmin & Biotivia™ Trans-Resveratrol).  HyVitality is dosed by weight.  More information at www.hyvitality.com.

5.  Vitamin C, 250mg.  Shar-Pei with excess HA may need more antioxidants like Vitamin C.  Also, I suspect that Shar-Pei may not synthesize adequate Vitamin C because Vitamin C and HA compete for similar biochemical synthetic pathways (both are formed by glucuronidation).

6.  Ensure Adequate Vitamin D3.  Active Vitamin D modulates the over-active toll like receptors (TLRs) in inflammatory disease, returning them to a more normal functionality. HA fragments bind to TLRs to activate the pro-inflammatory cascade. Shar-Pei on home-cooked diets or who are fed commercial diets and supplemented more than 10% of their calories with "extras" or who have active inflammation may have additional or increased need for Vitamin D3.  Need for Vitamin D3 in dogs has been estimated to be 50-475 IU per 10 lbs of body weight per day.  Most dogs on commercial diets get at least this in their diets but more may be needed if a dog is not on a balanced commercial dog food, has severe allergies, arthritis or chronic inflammation.  Discuss baseline testing with your veterinarian if you are concerned that your dog may need supplementation.

7.  Thyroid Function:  Treat any signs of secondary hypothyroidism with thyroid supplementation.  Common signs include very sparse or missing coat, particularly along the back and inside of the thighs and hindquarters, with a generally brittle, lighter coat on the torso.  HA fragments may down-regulate TSH releasing hormone via TLR2 binding, leading to clinical hypothyroidism characterized by low or low normal TSH and very low to low normal T3/T4 and I am looking this in Shar-Pei now.  Response to therapy will be softer, thicker, and richer colored fur with hair re-growth, especially on hindquarters, and improved overall health and activity if the dog is functionally hypothyroid.   Your veterinarian will monitor therapy to keep T4 below 4 µg/dL.

8.  Probiotics and attention to bowel health.  Skin and bowel are the immune system's biggest barriers and they are both HA rich areas.  Inflammatory bowel diseases including colitis are very common in the breed.  Some cases of FSF flare-ups and increased frequency of fever events have responded to treatment directed to eliminating over-growth of pathogenic GI bacteria in IBD patients or stress colitis.  (If diarrhea is frequent or persistent, discuss diagnosis and possible treatment with prescription drugs with your veterinarian.)

9.  Fanatical attention to skin and ear issues.  Bathing by shampoo or washcloth wipe-downs as needed (microfiber dust cloths work well) - up to daily when skin is inflamed and at least every 2 weeks in a "healthy" Shar-Pei. Remove superficial yeast, bacteria (potential sources of hyaluronidases, enzymes that damage HA) and allergens like pollens, molds, dust that may activated mast cells.  At least weekly ear cleaning/flush unless the Shar-Pei has a large, open, healthy ear canal.

10.  Low dose 81 mg aspirin: ¼ - ½  tablet per day in dogs with no signs of gastric upset.  Platelet derived growth factor might be an important mediator in their disease and aspirin also decreases risk of thromboembolic events.  Be cautious as the breed has an increased risk for GI ulceration.

11.  Detect problems early: Your veterinarian should see your Shar-Pei regularly for a complete physical examination and regular, routine monitoring of first morning urine with urinalysis (UA) as well as a CBC, blood chemistry profile and T4.

Eliminating inflammatory triggers, supporting healthy hyaluronan, reducing silent chronic inflammation wherever possible, providing good nourishment and playful daily exercise are key to Shar-Pei health.

July 2011

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