Retrospective Evaluation of Three Treatment Methods for Primary Hyperparathyroidism in Dogs

Introduction

In dogs with naturally occurring primary hyperparathyroidism, hypercalcemia develops secondary to autonomous production of parathyroid hormone (PTH).^1,2 The condition is most commonly caused by a solitary parathyroid gland adenoma.^3,4 Less commonly, the condition develops as a result of a parathyroid gland carcinoma or autonomously functioning hyperplastic parathyroid gland(s).⁵ About 10% of afflicted dogs have two abnormal parathyroid glands, either simultaneously or sequentially.^6,7

Naturally occurring primary hyperparathyroidism is usually suspected in a dog with hypercalcemia, mild clinical signs, and a serum phosphorous concentration within or less than the reference range.⁸ Serum PTH concentrations within or above the reference range help confirm the diagnosis.^9–11 In the past two decades, cervical ultrasonography has been used as a diagnostic aid for dogs with hypercalcemia.¹² Dogs with primary hyperparathyroidism usually have a solitary round or oval hypoechoic mass in close association with one thyroid lobe.^6,7,9,12,13 Abnormal parathyroid nodules usually measure 4 to 6 mm, but they can be as large as 20 mm in their greatest dimension.^6,7,9,12,13 Once the condition has been confirmed, surgical removal of the abnormal parathyroid gland or glands has been a permanent treatment option. More recently, novel therapeutic strategies using ultrasound-guided alcohol or heat ablation have been described, but reports have had limited numbers of dogs and short follow-up times.^14–16,a The purposes of this study were to evaluate and compare the treatment of primary hyperparathyroidism via surgery, ethanol ablation, and chemical ablation in a larger group of dogs and to determine the long-term efficacy of the three treatments.

Materials and Methods

Medical records of dogs diagnosed with naturally occurring primary hyperparathyroidism between November 1997 (date of the first ultrasound-guided percutaneous treatment procedure) and March 2005 were reviewed. Diagnosis of primary hyperparathyroidism was based on physical examination, phosphorous concentration within or below the reference range, repeatable hypercalcemia, PTH concentration within or above the reference range, and one or two parathyroid glands visualized on ultrasonography or at surgery.¹¹ All dogs that had surgery had excised tissue evaluated histopathologically. All dogs entered in the study were treated for primary hyperparathyroidism and had calcium concentrations evaluated once daily for 6 days and at 90 days after treatment. Dogs were excluded from the study if metastasis was seen on thoracic radiography.

Medical records for dogs with primary hyperparathyroidism were reviewed for signalment, clinical signs, total serum calcium concentrations, plasma ionized calcium concentrations, PTH concentrations, diagnostic imaging, treatment method, date of treatment, and response to treatment. Routine methods were used to perform serum biochemical analyses, CBCs, and urinalyses. Serum total calcium concentration was determined by colorimetric evaluation.^b Serum ionized calcium concentration was determined by ion-selective electrode analysis.^c Serum PTH concentration was determined by use of a validated, two-site immunoradiometric method that recognizes amino- and carboxy-terminal ends of the intact molecule.^9,10,d All PTH assays were performed in the clinical chemistry laboratory at the University of California, Davis,^e or at the endocrine laboratory at Michigan State University.^f Ultrasonography of the neck was performed with a 10-MHz linear, phased-array transducer and a standard ultrasonography machine.^g Arbitrarily, dogs with a parathyroid mass >12 mm at its greatest dimension were treated with surgery. Other treatments were chosen by the primary clinician after discussions with the owners.

Results

A total of 110 dogs were included in the study, and the signalment data are presented in Table 1. The most commonly affected breed was the keeshond (n=21), followed by the mixed-breed dog (n=18), Labrador retriever (n=9), German shepherd dog (n=7), golden retriever (n=6), miniature poodle (n=6), shih tzu (n=5), Australian shepherd (n=4), Rhodesian ridgeback (n=3), and American cocker spaniel (n=3). The remaining 28 dogs comprised 18 other breeds. Each treatment group was composed of numerous breeds. The most common clinical signs reported in the dogs are presented in Table 2. Hypercalcemia was an incidental finding on routine geriatric or preanesthetic laboratory screenings in 42 of the 110 dogs. The pertinent laboratory findings are presented in Table 3.

Cervical ultrasonography was performed on all 110 dogs, and all dogs had one (n=96) or two (n=14) masses visualized that were consistent with abnormally enlarged parathyroid glands. Of the 14 dogs with two parathyroid nodules identified, nine had bilateral masses and five had two ipsilateral masses. Twelve dogs had a parathyroid mass that measured >12 mm. Forty-seven dogs were treated with parathyroidectomy, 15 dogs were treated with ethanol ablation, and 48 dogs were treated with heat ablation. The 47 dogs treated with surgery had 56 nodules based on ultrasonography. Thirty-eight dogs had a single nodule, and nine dogs had two nodules (bilateral n=7, ipsilateral n=2). The 15 dogs treated with ethanol ablation all had a single nodule. The 48 dogs treated with heat ablation had 53 nodules; 43 dogs had a single nodule, and five dogs had two nodules (bilateral n=3, ipsilateral n=2). The number of successful and failed treatments and follow-up times after therapy are presented in Table 4. Fisher’s exact tests showed no significant differences in the outcomes between parathyroidectomy and heat ablation (P=0.71) and between heat ablation and ethanol ablation (P=0.12). A significant difference in outcomes was found between parathyroidectomy and ethanol ablation (P=0.03).

Hypercalcemia resolved in 44 of the 47 dogs treated with one surgery within 1 to 6 days (mean 1.6±1.1 days). Either serum total or ionized calcium concentration returned to normal within 48 hours in 29 dogs. Hypercalcemia resolved in 3 to 4 days in 13 dogs and in 4 to 6 days in two dogs. Hypercalcemia failed to resolve after parathyroidectomy in three dogs. Two of these three dogs were not treated again, and one had a second parathyroidectomy 30 days later, with complete resolution of the hypercalcemia within 48 hours. The two dogs not treated again had no parathyroid tissue identified in histopathological samples. Based on pathology of the 54 surgically excised glands from 45 dogs, parathyroid adenoma was the most common lesion (n=42), followed by glandular hyperplasia (n=9) and adenocarcinomas (n=3).

Twelve of 15 dogs were treated successfully with one ethanol ablation, with hypercalcemia resolving in 1 to 4 days (mean 1.9±1.4 days). Either serum total or ionized calcium concentrations decreased to the reference range values within 48 hours in 10 dogs. Hypercalcemia resolved in 3 days in one dog and in 4 days in one dog. One dog remained hypercalcemic after an initial ethanol ablation, but it responded to a second ablation procedure, and the calcium concentration returned to normal within 48 hours. Two other dogs remained hypercalcemic after two separate percutaneous ethanol injections. A total of 18 ablation procedures were performed in the 15 dogs, with five considered to be failures.

Forty-three of 48 dogs treated with percutaneous ultrasound-guided heat ablation had resolution of hypercalcemia after one treatment, and one dog responded after a second treatment. Two dogs had ipsilateral masses, and both masses were ablated at the same time, with resolution of the hypercalcemia. Three dogs had bilateral masses. Two of these dogs had one nodule ablated initially, and the second nodule was ablated 30 days later. The procedures were staged in order to minimize the risk of bilateral laryngeal paralysis. Hypercalcemia resolved after the second gland was treated in both dogs, and these dogs were treated as single treatment successes. The third dog had complete resolution of hypercalcemia after an ablation procedure was performed on the larger of the two parathyroid masses. The smaller gland, therefore, was not treated, and hypercalcemia did not recur.

A total of 43 dogs were treated successfully with one heat ablation treatment, with hypercalcemia resolving in 1 to 6 days (mean 2.3±1.3 days). Mean time to resolution was significantly longer than that for the surgically treated dogs (P=0.001) and the ethanol-treated dogs (P=0.004). Either serum total or ionized calcium concentration decreased to reference range values within 48 hours in 32 dogs, while six dogs required 2 to 4 days, and six dogs required 4 to 6 days. Hypercalcemia failed to resolve in one dog after the initial treatment, but it resolved after a second treatment. The calcium concentration returned to normal within 48 hours of the second treatment. Four other dogs failed to respond to one percutaneous heat treatment, and they were not treated a second time. A total of 49 treatments were performed, with five considered to be failures.

It was interesting to note that in the heat ablation treatment group, three of the four treatment failures were among the first 24 procedures performed. If the dogs are separated into three groups of 16 based on chronology of treatment, the first group had three treatment failures, the second group had one, and the third group had none. If the dogs treated with ethanol ablation are added to those treated with heat ablation (63 dogs total), there were six treatment failures among the first 31 dogs treated and one treatment failure among the second 32 dogs treated.

Hypocalcemia was the most common complication noted after treatment in all three treatment groups. Other complications were few and are presented in Table 5. Delayed recurrence of hypercalcemia was noted in two dogs treated with surgery. Hypercalcemia recurred in one dog 305 days after surgery and at 687 days after surgery in the other dog. Both dogs underwent a second surgery for a parathyroid gland adenoma contralateral to the initial mass. Hypercalcemia resolved in both dogs after the second procedure. Relapse of hypercalcemia also occurred in one dog 477 days after ultrasound-guided heat ablation treatment. This dog underwent a second successful heat ablation treatment of a contralateral parathyroid gland.

Discussion

Overall, the responses to all three treatment modalities for primary hyperparathyroidism were good. There was no statistical significance between the success rates for parathyroidectomy and heat ablation, but there was a statistical significance between the success rates for parathyroidectomy and ethanol ablation. There was no statistical significance between the success rates for heat ablation and ethanol ablation. The total number of dogs in the ethanol ablation group was less than the total number of dogs in the surgery and heat ablation groups, which may have affected the statistical outcome between the groups. Dogs treated with heat ablation had similar outcomes to dogs treated with parathyroidectomy.

Surgery (i.e., parathyroidectomy) has been used as a treatment for primary hyperparathyroidism for decades.^3,8 Previous studies have not reported any failures.^3,16 In the current study, three surgeries failed to control hypercalcemia, and no parathyroid tissue was detected on histopathology of these cases. These surgical failures arose from an inability to locate the abnormal parathyroid tissue. Despite ultrasonographic identification of a mass, the ultrasound may not have correctly identified the abnormal gland.

Ethanol ablation for dogs with primary hyperparathyroidism was first described in 1999.¹⁴ In the original study, a total of nine treatments were performed in eight dogs, and seven treatments were successful.¹⁴ Six dogs were evaluated 6 months after therapy, and all had normal calcium concentrations.¹⁴ A more recent study in 2005 discussed five dogs treated with ethanol ablation; two dogs had a decline in calcium concentrations, but all dogs continued to have hypercalcemia and were considered failures.¹⁶ These two studies had very different outcomes. The dogs in the earlier study had similar outcomes to the dogs in the study reported here. The current study contained a larger number of dogs treated with ethanol ablation, with longer follow-up times. Needle insertion into a parathyroid tumor using ultrasound guidance is a relatively new approach. It is often necessary to redirect the needle several times during either ethanol or heat ablation when attempting to ablate all abnormal tissue.^14,15 In the study reported here, the incidence of ethanol treatment failure may have been minimized, in part, by having an experienced radiologist involved with each procedure.

One previous report exists on the use of heat ablation for primary hyperparathyroidism in dogs.¹⁵ In that study, nine dogs had a total of 12 treatments, and eight were successful.¹⁵ These dogs were followed for 3 to 8 months.¹⁵ The dogs in the current study had similar outcomes, and there were more dogs in the current study, with longer follow-up times. When ultrasound-guided heat ablation was used to treat hyperthyroidism in cats, the procedure controlled the disease for a mean of 4 months.¹⁷ It was important, therefore, in the current study to evaluate long-term efficacy of all treatments. The median follow-up time for all of the dogs in the study reported here was 560 days. Both percutaneous ethanol and heat ablation procedures provided long-term control of the hypercalcemia in the majority of cases. The decrease in treatment failures with the ultrasound-guided procedures over time may have indicated that improved skill gained from experience had a positive impact on outcome.

All dogs that had a successful procedure performed, regardless of type, had calcium concentrations within the reference range within 6 days after the therapy. In previous studies of dogs treated for primary hyperparathyroidism with surgery, ethanol ablation, or heat ablation, the majority of dogs had resolution of hypercalcemia within 48 hours of therapy, which is similar to the dogs reported in this study.^14–16 In the current study, calcium took a significantly longer time to return to normal after heat ablation when compared to times after surgery and ethanol treatment. The statistical difference may have occurred because of the pathophysiology of heat ablation.¹⁸ Thermal necrosis causes cell death that can continue to occur after the heat ablation procedure is terminated. The effects of parathyroidectomy are immediate, because the tissue is excised. The time difference between heat ablation and chemical ablation may have arisen from differences between thermal necrosis and coagulation necrosis.¹⁵ More tissue may be affected more rapidly with ethanol ablation compared to heat ablation. The end points for both heat ablation and ethanol ablation are subjective, and this could also affect the amount of tissue treated.

Biochemical hypocalcemia was fairly common after all three treatment modalities (n=41; 37%); however, clinical signs of hypocalcemia were rare (n=12; 11%). In a previous study on dogs with primary hyperparathyroidism treated with surgery, 11 of 19 dogs had laboratory hypocalcemia, nine dogs had clinical hypocalcemia, and one died of tetany.³ These findings may have prompted closer monitoring for hypocalcemia and more aggressive treatment with vitamin D and calcium. In previous studies, four of eight dogs treated with ethanol ablation and five of eight dogs treated with heat ablation had hypocalcemia.^14,15

In the current study, complications other than hypocalcemia were infrequent. There were no observed side effects noted in any dogs after parathyroidectomy. Other mild complications occurred in a small number of dogs after both types of ultrasound-guided treatment modalities. Leakage of the ethanol or extension of thermal necrosis from the parathyroid gland may have extended into the surrounding tissues and caused damage to structures, such as the recurrent laryngeal nerve and vagosympathetic trunk.¹⁵ Laryngeal examinations were not performed, so laryngeal paralysis was not documented in any dogs that were coughing or had changes in bark. In previous studies, two of eight dogs had dysphonia after ethanol ablation, and one of nine dogs had dysphonia after heat ablation.^14,15 Previous studies did not document Horner’s syndrome or coughing, unlike the current report.

There were several limitations to this retrospective study. Numerous primary clinicians, radiologists, and surgeons were involved in all of the cases, so each case was managed differently. No cytological or histopathological samples were submitted from dogs treated with ethanol or heat ablation. Recheck examinations were often performed by local veterinarians, and total calcium concentrations were used to monitor the response to therapy in most cases. Ionized calcium concentrations were not commonly measured as part of the follow-up process.

Conclusion

Dogs with primary hyperparathyroidism were treated with one of three treatment methods. Parathyroidectomy was the most successful treatment, with no complications other than hypocalcemia. Percutaneous ultrasound-guided ethanol ablation was the least successful treatment and had the most side effects. This study showed that heat ablation is an effective alternative to surgery, as there was no statistical significance between the outcomes in these two groups of dogs. There were more treatment failures in the first group of dogs treated with ethanol and heat ablation compared to the third group of dogs, suggesting that there is a learning curve with these two ultrasound-guided procedures.