Canine Primary Hyperparathyroidism

Primary Hyperparathyroidism (PHPT) is thought to be the second most common cause of pathologic hypercalcemia (increased serum calcium) in dogs. It is caused by an inappropriate secretion of parathyroid hormone (PTH) by autonomously functioning ''chief'' cells within the parathyroid glands in the neck of the dogs. There are four parathyroid glands, two on each side. They are called ''para'' thyroid because they are next to the thyroid gland but functionally they are distinct from the thyroid gland. Thus parathyroid diseases are not connected to thyroid diseases like hyperthyroidism or hypothyroidism. Parathyroid hormone is an important factor in maintaining calcium homeostasis (normal calcium concentrations and function). Dr. Goldstein with Keeshond When secreted, PTH causes an increase in serum calcium via bone resorption, decreased calcium excretion from the kidneys and increased vitamin D metabolism. Vitamin D causes increased absorption of calcium from the intestines. Parathyroid hormone secretion by parathyroid chief cells is normally regulated tightly by serum ionized (or unbound) calcium. Normally, if the concentration of ionized calcium rises, PTH secretion is then decreased through negative feedback, allowing the calcium concentration to go back to normal. In PHPT, PTH secretion persists despite increased calcium concentrations resulting in many instances in severe, life threatening hypercalcemia. Most cases of canine PHPT (80-85%) result from a solitary parathyroid adenoma, a solitary benign tumor of the parathyroid gland. Parathyroid hyperplasia affecting multiple glands occurs in most of the remaining cases while the malignant parathyroid carcinoma is considered to be very rare in dogs. This condition affects middle aged to older dogs with a mean age of approximately 10.5 years, according to the existing veterinary literature without taking specific breeds into account. In the early phases of this disease, the affected dogs tend to be relatively free of symptoms except for increased drinking and urination, in addition to a gradual onset of weakness, lethargy, shaking and sometimes weight loss. Many have concurrent calcium containing urolithiasis (bladder or kidney stones). As the hypercalcemia becomes more profound, organ damage occurs, including possible damage to bones as well as severe kidney damage. If the hypercalcemia is left untreated, this secondary kidney disease can eventually lead to severe renal failure and death. The diagnosis of PHPT is based on the finding of normal or increased serum PTH concentrations in the presence of increased total and ionized calcium concentrations. The enlarged parathyroid gland or glands can frequently also be identified with cervical (neck) ultrasound. The treatment of PHPT involves surgical removal or ultrasound guided chemical ablation or heat ablation of the affected parathyroid gland. When performed early in the disease, prior to the onset of renal failure and with appropriate post operative care and monitoring, this treatment is typically very successful with a relatively low percentage of reoccurrence.

The genetics of Canine Primary Hyperparathyroidism

Prior to our recent study, little was known about the genetics of this condition in dogs despite obvious breed predispositions reported in the literature. In 1984 a suspected familial form of neonatal hyperparathyroidism was reported in a litter of German Shepherd puppies. An autosomal recessive mode of inheritance was suspected. Despite this early report, this form of early onset PHPT is extremely rare. In a recent survey of 168 dogs diagnosed at the University of California at Davis (UCD) over a span of 20 years, no dog was younger than four years of age. The disease is especially concerning from a breed perspective because of the adult to geriatric onset of this condition and our inability to recognize affected dogs prior to breeding. The breed that is by far the most common in large surveys of dogs with this disease is the Keeshond. This includes approximately 40% of the dogs diagnosed at the Cornell University Hospital for Animals in the last 10 years. In 2001 a review of cases of canine PHPT was published based on samples submitted to the Diagnostic Endocrinology Section, Animal Health Diagnostic Laboratory, Michigan State University. In this review the number of positive cases was reported for each breed, and was compared to the average number of dogs of each breed registered with the American Kennel Club over the years of the study. The Keeshond was by far the most likely breed to be affected with PHPT and is approximately 50 times more likely to be diagnosed with the disease than the average breed. The only other two breeds that had over 100 positive samples and a higher than average chance of getting the disease were Golden Retrievers (1.6 times more likely) and Dachshunds (2 times more likely). Based on this we decided to investigate the genetic basis for PHPT in Keeshonden. It is possible that this disease is hereditable in other breeds as well.

Mode of Genetic Transmission

Most people are familiar with genetic diseases that are autosomal recessive in nature, and genetic test results that arrive with a designation of ''Clear, Carrier or Affected.'' The transmission of PHPT in the Keeshond is autosomal dominant. An abnormal gene from one parent is all that is necessary to potentially pass on the disease to the offspring, regardless of whether or not the other parent also carries the PHPT gene. With an autosomal dominant gene, there isn't a carrier status. Either a Keeshond has the PHPT gene, or it doesn't. If a Keeshond that has the defective autosomal dominant PHPT gene is used for breeding, 50% of their offspring will also have the gene, while 50% will not. If a Keeshond with the defective gene is bred to another Keeshond who also has the defective gene, 50% of the offspring will have one copy of the defective gene, 25% will have two copies of the normal gene and 25% will have two copies of the defective PHPT gene. Based on our research it appears that embryos in this last group with two copies of the defective gene may actually not survive in utero, resulting in smaller litter sizes for this type of breeding.

This disease affects older Keeshonden with what is known as ''age dependent penetrance.'' This means that the test does not identify clinical disease at the time of testing; it indicates the presence of the defective gene, or the genetic potential to develop the disease later in life. The vast majority of Keeshonden with the defective gene will develop PHPT if they live long enough. All the Keeshond samples that were submitted for the study have been tested in our laboratory. Every dog with a diagnosis of PHPT has been positive for the defective gene. Seven percent of the unaffected

Keeshonden that were submitted also have been found to be positive for the gene. Again, this does not mean that if a Keeshond was one of the seven percent that it will definitely get PHPT, but if they live long enough, most of them probably will.

The Genetic Test for PHPT

The test that we are offering for this disease tests for the form of the gene that we have found to be highly associated with the disease. A NEGATIVE result means that the affected form of the gene is not present and the dog is very unlikely to develop the disease. A POSITIVE result means that the affected form of the gene is present in the tested dog. Dogs that possess this form of the gene are very likely to develop primary hyperparathyroidism as they become older even if they are healthy at the time this test was performed. Frequent monitoring of serum calcium concentrations is recommended to allow early detection of the disease in dogs positive for the PHPT gene.

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