Lymphocytic Thyroiditis - It's Not Just Hypothyroidism

By Cynthia Roethel
RRCUS Health & Genetics Committee Senior Chair

Lymphocytic thyroiditis is the Rhodesian Ridgeback’s most common health disorder.
It is an autoimmune disease (1-4).

Most people refer to it as “hypothyroidism,” which makes it sound less threatening. Others take a more cavalier approach, referring to it as “just hypothyroidism” and commenting on how easy it is to treat with pills that only cost a few cents a day. Some continue to minimize its importance by noting it certainly has less impact than diseases like epilepsy or hip dysplasia, where dogs cannot live a normal life. And still others argue the heritability of this disease and supplement their dogs with iodine and seaweed, convinced there is something lacking in the diet, when in fact research suggests that excessive amounts of iodine can cause a significant impairment of thyroid function and hypothyroidism. (5)

All of the above rationalizations have been made to justify breeding affected dogs. 

Hypothyroidism in Rhodesian Ridgebacks is caused by lymphocytic thyroiditis and it is much more that “just hypothyroidism” (2-4, 6-8). Rarely – very rarely -- is there another cause for hypothyroidism in Rhodesian Ridgebacks.

Lymphocytic thyroiditis is an autoimmune disease, which means the body treats the thyroid gland as a foreign object because the immune system fails to recognize the thyroid gland as part of itself.  It is referred to as lymphocytic thyroiditis because the thyroid gland is destroyed by T-lymphocytes (a type of white blood cell involved in cellular immune function) that infiltrate the gland by means of specific thyroid autoantibodies. While the thyroid is the target organ in this case, the primary disease is that of the autoimmunity, the failure of self-tolerance. The attack on the thyroid gland and its eventual failure is the manifestation of the autoimmune disease.

Autoimmune disease is a spectrum of diseases that can target one or more body tissues (1,6). The condition can be limited to a particular organ, as in lymphocytic thyroiditis; or it can affect a region of the body or even the entire body. The effect can be minimal – where daily pills to replace thyroid hormone are all that are needed – or the effect can be catastrophic, depending on the extent the body is affected. (1-2, 6-8)  Often more than one autoimmune disease will be seen in the same dog. (2, 6-8).  This makes perfectly good sense as genes tend to be inherited in groups, or haplotypes (1, 2,9,10).

Breeding dogs affected with lymphocytic thyroiditis -- whether symptomatic or even if the only indicator is an elevated TGAA autoantibody level -- is breeding an “autoimmune dog” that can present with and pass on the genetic susceptibility to a myriad of autoimmune problems to the offspring.

There are several autoimmune diseases that can be screened for by determining if a dog has specific autoantibodies against the target tissue involved. Lymphocytic thyroiditis is one of those diseases detected only with a full thyroid panel, including specifically the all-important TGAA autoantibody test (2-4, 7,8). Though not a DNA marker, the TGAA antibody test serves as a marker for lymphocytic thyroiditis.  We can identify dogs early in life with these autoantibodies and remove them from our breeding programs.

Now carry this one step further. Given the fact that more than one autoimmune disease can manifest in the same dog, you can think of thyroiditis testing as a marker for autoimmune disease, not “just hypothyroidism.” By breeding away from lymphocytic thyroiditis, you are breeding away from autoimmune disease (6, 7).

Dr. Jean Dodds of Hemopet, who does many Ridgeback thyroid evaluations, includes the T3AA and T4AA circulating autoantibody data in assessing for lymphocytic thyroiditis. She says that up to 8 percent of affected dogs are TgAA negative. This false negative can result from a type of receptor on the thyroglobulin molecule not binding to the TgAA marker. In this small subset of affected but TgAA-negative dogs, Dr. Dodds states that persistently elevated levels of T3AA and T4AA indicate the presence of lymphocytic thyroiditis.

A FAQ page on the Michigan State University web site entitled “Thyroid Function in Dogs,” which has now been removed, acknowledged that T3AA and T4AA are subsets of TgAA and that all three autoantibodies are markers for lymphocytic inflammation of the thyroid gland. According to MSU, these subsets are present in only a portion of the TgAA positive patients, implying that T3AA and T4AA are only seen occasionally in TGAA-positive patients. 

In February 2006, the RRCUS Health and Genetics Senior chair had a discussion on this topic with   K.R. Refsal, DVM, PhD, of the Diagnostic Center for Population and Animal Health at MSU. He indicated that T3AA and T4AA were originally done to give veterinarians more data to help interpret results. He added that increases in T3AA and/or T4AA might be a result of nonspecific binding, where the marker specific for a particular antibody binds to something other than the target antibody.  As a result, this can give a falsely high reading.  Repeat testing at a later date often shows normal antibody levels.   According to Dr. Refsal, the reasons for persistent elevations of T3AA and T4AA with negative/normal TGAA are not know. 

Breeders must understand that a dog will received OFA clearance if T3AA and/or T4AA are elevated out of the normal range so long as the TGAA is negative. Due to conflicting opinions on the significance of elevated T3AA and T4AA antibodies, the RRCUS H&G committee is collecting data on the incidence of this phenomenon in the breed to determine whether or not Ridgebacks with these elevations progress to develop lymphocytic thyroiditis.

What causes autoimmune disease? It is a combination of the genetic and environmental influences that override normal immune function and cause failure of self-tolerance (1, 6). To those inbreeding and linebreeding purebred dogs, this equates to genetics! We know that the major histocompatibility complex (MHC) genes are associated with the incidence of specific autoimmune diseases in humans (1). Very recent and landmark research has found the MHC to be associated with lymphocytic thyroiditis in several dog breeds, including the Rhodesian Ridgeback  (9, 10).

The heritability of autoimmune disease is indisputable. But while a genetic predisposition must be present in order for a dog to develop an autoimmune disease, it appears that for the disease to manifest there must be one or more specific environmental insults to the immune system (1, 6). Insults can range from toxin, drugs, stress, hormonal changes, viral and other infectious diseases, vaccinations, etc. Keep in mind that these do not cause autoimmune disease, but rather are the influences that “trigger” the disease the dog is genetically predisposed to develop. If the genetic predisposition were not present, these environmental triggers would not result in autoimmune disease. (1, 6). 

The following are some of the frequently seen autoimmune diseases that occur in the canine community.  There are others. These can occur independently or in combination (1, 6-8, 11).

Autoimmune hemolytic anemia (AIHA), also called immune mediated hemolytic anemia (IMHA). Antibodies formed against antigens in the cell membrane of the red blood cause the red cells to agglutinate and rupture. The resulting anemia decreases the dog's ability to provide enough oxygen for cell function throughout the body. (6,7)

Immune-mediated thrombocytopenia (IMTP or ITP). This results in a dangerously low level of platelets.  The low platelet levels lead to spontaneous bleeding, often nose bleeds or bleeding just under the skin and mucous membranes, or in association with surgery or trauma.  (Often seen with AIHA, SLE and RA.) (6,7)

Autoimmune thyroiditis (hypothyroidism) is generally found with the other autoimmune  diseases or may occur by itself. Loss of thyroid hormones is manifested early by behavioral changes - aggression, hyperactivity, anxiety/fear, compulsive behaviors, phobic behaviors; allergies and reduced resistance to bacterial, viral, fungal and protozoal infection, which often manifests as skin and respiratory disorders. Seizure disorders are also often related to low thyroid levels. As the disease progresses, lethargy, obesity, loss of hair/poor coat and infertility are more common. (7,11)

Hypoadrenocorticism (Addison's disease): The adrenal gland produces hormones that are needed to maintain proper cell function. Their loss is seen as muscle weakness and eventually heart failure as the heart's muscle cells can no longer produce the neurological impulses needed for the heart contractions. Gastrointestinal function is usually affected as well, and weight loss is frequently seen. The symptoms can be subtle until the dog just collapses in shock. Animals are less able to cope with mild, everyday occurrences and hide, refuse to eat, and show other symptoms of stress. (6, 8)

Systemic lupus erythematosus SLE:  This can be hard to diagnose as it can present as a disease of the skin, mucous membranes, nails, kidney, joints or any combination of these. SLE can also affect the brain producing signs of cognitive dysfunction. (6)

Symmetrical lupoid onychodystrophy is a manifestation of SLE reported in Rhodesian Ridgebacks where the nails crumble and eventually fall off.  The nails beds bleed and it is very painful.

Rheumatoid Arthritis (RA) results from rheumatoid factor attacking the joint spaces, causing an inflammatory response, joint swelling and pain. The collagen and cartilage of the joint breaks down and is eventually replaced by fibrin, which fuses the joints.

Myasthenia gravis results in a loss of muscle function because muscles no longer can receive neurological signals. There is a loss of muscle mass, because of disuse, weakness and a reluctance to move. The esophagus will lose muscle tone as well and may enlarge, causing megaesophagus. Even when treated, dogs are very prone to die of aspiration pneumonia due to megaesophagus. Untreated dogs will eventually lose the use of swallowing and respiratory muscles.

Autoimmune myositis. In polymyositis, there is often generalized weakness worsen by exercise. Most frequently, the muscles over the top of the head waste away. Fever and depression are common. Concomitant SLE, RA and myasthenia gravis have been reported in dogs. Masticatory muscle myositis is limited to the chewing muscles as antibodies are formed to that particular type of muscle fiber.

References:

1.  Sinha AA, Lopez MT, McDevitt HO.  “Autoimmune diseases: the failure of self tolerance.” Science 248:1380-1388, 1990.    

2. Happ GM.  “Thyroiditis - A model canine autoimmune disease”.  Adv Vet Sci Comp Med  39: 97-139, 1995.

3. Nachreiner RF, Bowman M, Refsal KR, Graham PA, Provencher-Bolliger A. Canine Hypothyroidism:  “Prevalence of Positive TgAA in 57 Laboratory Samples From Rhodesian Ridgebacks” Animal Health Diagnostic Laboratory, College of Veterinary Medicine, Michigan State University, East Lansing, MI,  2001

4.  Nachreiner RF, Refsal KR, Graham PA, Hauptman J, Watson GL. “Prevalence of autoantibodies to thyroglobulin in dogs with nonthyroidal illness”, Am J Vet Res 59:951-5, 1998.

5.  Castillo VA, Lalia JC, Junco M, Sartorio G, Marquez A, Rodriguez MS, Pisarev MA. “Changes in thyroid function in puppies fed a high iodine commercial diet”.  Vet J. 161(1):80-4, 2001.

6.  Dodds WJ. “Complementary and alternative veterinary medicine: the immune system.” Clin Tech Sm An Pract 17: 58-63, 2002.

7. Dodds WJ.  “Estimating disease prevalence with health surveys and genetic screening.” Adv Vet Sci Comp Med, 39: 29-96, 1995.

8.  Dodds WJ. “Autoimmune thyroiditis and polyglandular autoimmunity of purebred dogs.”  Can  Pract 22 (1): 18-19, 1997.

9. Happ GM, Ollier W, Kennedy LJ. “Genetic determinants of susceptibility to hypothyroid disease in dogs.” AKC Research Foundation Report, Sept 2005.

10. Kennedy LJ, Quarmby S, Happ GM, Barnes A et al. “Association of canine hypothyroid disease with a common major histocompatibility complex DLA class II allele.” Tissue Antigens (in press), 2006

11. Dodds WJ, Aronson LP.  “Behavioral changes associated with thyroid dysfunction in dogs.”  Proc Am Hol Vet Med Assoc, 80-82, 1999.