Ultrasound guided Percutaneous Ethanol Injection PEI for the treatment of

Ultrasound-guided Percutaneous Ethanol Injection (PEI) for the treatment of primary hyperparathyroidism in a dog Author: Todd M. Bishop DVM 2003 Advisor: Richard Goldstein DVM, DACVIM Senior Seminar Paper Cornell University College of Veterinary Medicine September 25th, 2002 “Sadie-Mae”, a 10 year-old spayed female mixed breed dog, presented to the Small Animal Medicine Service for inappetance, lethargy, weight loss, incontinence, occasional constipation and questionable polyuria. Physical exam was unremarkable except for some mild hepatomegaly and slightly enlarged popliteal lymph nodes bilaterally. A complete blood count was within normal limits. A serum chemistry profile indicated a mild hypomagnesemia and a marked hypercalcemia. A parathyroid panel revealed a mildly elevated intact PTH level, a marked elevation in ionized calcium and a PTHrP level that was within normal limits. Cervical ultrasound revealed a small, focal, round-oval hypoechoic nodule in the thyroid tissue on the right side. These results suggested a diagnosis of primary hyperparathyroidism. Sadie-Mae’s owners opted to pursue therapy using ultrasound-guided percutaneous ethanol injection to the chemically ablate the affected parathyroid gland. “Sadie-Mae” a 10-year spayed female German Shepard-Collie cross presented to the Small Animal Medicine service at the Cornell University Hospital for Animals with a chief complaint weight loss, inappetance and lethargy. Thirteen days prior to admission, the families other dog died of complications resulting from a bleeding gastric ulcer. Since that time, “SadieMae” had become progressively more lethargic and would only eat when hand fed. Anamnesis revealed that “Sadie-Mae’s” owners acquired her as a puppy from a neighbor ten years prior. She was allowed to be outside without supervision, but she was never known to wander off the property. She had no significant travel history. She had recently been immunized for Rabies, Distemper and Lyme’s disease. She was not on any flea, tick or heartworm preventatives and had not been dewormed recently. She was fed a reputable commercial dog food, but despite proper feeding, “Sadie” had lost approximately 6 lbs. in 6 months. “Sadie’s” owners thought that she might have recently become polyuric, but that finding was confounded by the fact that she had been experiencing some urinary incontinence for approximately a year and a half. She was never seen to have stanguria, but would occasionally experience tenesmus and constipation. According to her owners, “Sadie” was never exposed to any potential toxins, such as rodenticides. The physical exam was quite contrary to the clinical history. In the exam room, “Sadie” was bright, alert and responsive. One might even describe her as excited or anxious at times. “Sadie” was in good flesh, euhydrated and slightly over-weight. Thoracic auscultation revealed 2 no cardiopulmonary abnormalities. Abdominal palpation revealed a mild hepatomegaly, but was otherwise benign and non-painful. Additionally, she had a very mild bilateral popliteal lymphadenopathy. No musculoskeletal nor neurologic deficits were appreciated on physical exam. At this point in the case, “Sadie-Mae’s” problem list included: weight loss, inappetance, lethargy, incontinence, possible polyuria and occasional constipation. All of these problems are very nonspecific and may be the result of various etiologies. None of these clinical signs are pathognomonic for any one disease. Blood work done at the referring veterinarian included a complete blood cell count (CBC) and serum chemistry profile. The results of the CBC were completely within normal limits. The chemistry panel revealed a mild hypomagnesemia (1.3 mEq/L; reference range, 1.5 to 2.5 mEq/L) and a profound hypercalcemia (15.1 mg/dL; reference range, 8.9 to 11.4 mg/dL). Albumin levels were within normal limits (3.6 g/dL; reference range, 2.7 to 4.4 g/dL) as were serum phosphorus levels (2.6 mg/dL; reference range, 2.5 to 6.0 mg/dL). Whenever calcium abnormalities occur, it is impairative that the clinician check both the albumin and phosphorus levels as both can impact calcium concentrations quite profoundly. Hypomagnesemia can occur for a multitude of reasons including decreased uptake, increased loss or redistribution. Inadequate dietary supplementation of magnesium, like other vitamin and mineral disorders, is uncommon due to number of nutritionally balanced pet foods on the market today. Occasionally, dogs with malabsorptive disease or chronic diarrhea may become hypomagnesemic. More commonly, hypomagnesemia develops secondary to profound loss of magnesium ions in the urine. Diuresis with loop diuretics, osmotic diuresis (glucose, mannitol) or chronic parenteral fluid therapy with magnesium free solutions can cause a significant hypomagnesemia. Additionally, any insult to the renal tubular epithelium (aminoglycosides, ethylene glycol) may destroy the kidney’s reabsorptive capabilities leading to various electrolyte abnormalities, including hypomagnesemia. Redistribution or transcellular shifts of magnesium 3 ions has been associated with refeeding syndromes and insulin therapy1. Finally, several endocrinopathies have been associated with hypomagnesemia including: Diabetes mellitus, hyperthyroidism, hyperadrenocortisim, primary hyperparathyroidism, and inappropriate ADH secretion1. Clinical manifestations of hypomagnesemia typically occur when serum magnesium levels are less than 1.2 mg/dL, but the rate decline is also a factor1. Depending on the severity of the magnesium deficit, hypomagnesemia can have a profound affect on both the neuromuscular and central nervous system (CNS). It is thought that hypomagnesemia may lower the depolarization threshold in excitable cells similar to hypocalcemia. Additionally, low concentrations of intracellular magnesium may enhance the release of calcium from the sarcoplasmic reticulum thereby promoting muscle contraction. In some cases, hypomagnesemia may result in tetany-like signs including muscle tremors, spasm and fasciculations. Other patients may experience restlessness, hyperexcitability, ataxia, nystagmus or even generalized seizures1. Magnesium is thought to play a role in the regulation of transcellular shifting of electrolytes such as sodium and potassium. In hypomagnesemic states, cardiac arrhythmias may occur due to the inhibition of Na+/K+ ATPase and excessive efflux of potassium ions out of excitable cells. Magnesium normally acts to restrict potassium efflux out of cardiac myocytes by blocking the IK1 channel during depolarization. Electrocardiographic changes include peaked T waves and ST segment depression1. The peaked T waves may be the result of a relative extracellular hyperkalemia due to unblocked IK1 channels. Additionally, certain electrolyte deficiencies (hypocalcemia, hypokalemia) may remain refractory to supplementation until magnesium levels are normalized1. Therefore, magnesium levels should be evaluated in any patient that is refractory to electrolyte therapy. More important than the mild hypomagnesemia, was the profound hypercalcemia. This metabolic derangement, when seen, should automatically bring to mind six (6) differential diagnoses: hypercalcemia of malignancy, hypoadrenocorticism, primary hyperparathyroidism, 4 renal secondary hyperparathyroidism, hypervitaminosis D, and inflammatory (granulomatous) diseases. Hypercalcemia, regardless of etiology, can cause a variety of clinical signs similar to those seen in this case. Unchecked hypercalcemia may cause dogs to develop acute or acute-onchronic renal failure. High serum concentrations of ionized calcium may lead to acute renal tubular necrosis. This may be the result of renal vasoconstriction resulting in ischemic nephrons or the direct toxic effect of ionized calcium on renal tubular epithelium1. Additionally, dogs with protracted bouts of hypercalcemia, specifically are predisposed to developing nephrocalcinosis 1,2. This is specifically true in patients where the product of the total calcium concentration times the serum phosphorus concentration is greater than 70 (Ca2+ x Phos >70). Hypercalcemia may lead to decreased urine concentrating abilities due to impaired action of antidiuretic hormone (ADH) 2. Hypercalcemia through the disruption of ADH function in the collecting ducts, results in a form of nephrogenic diabetes insipidus (NDI) 1. These dogs produce hyposthenuric urine and experience medullary gradient washout. Loss of urine concentrating ability, together with ADH dysfunction, leads to polyuria. Hypercalcemia dogs experience a profound calciuresis predisposing them to developing calcium-oxalate urolithiasis1,2,3. Cystic calculi and nephrocalcinosis can often be visualized with the aid of radiography or ultrasound. Urolithiasis may predispose dogs to developing recurrent urinary tract infections (UTI). Cystic calculi often act as a nidus for infection. Similar to magnesium, calcium can have a seriously impact excitable cells. Hypercalcemia effectively raises or makes the threshold potential less negative thereby discouraging depolarization of excitable cells. Many dogs with hypercalcemia experience anorexia, vomiting and constipation due to decreased excitation of gastrointestinal smooth muscle1,2,3. Similarly, some hypercalcemic dogs present with signs of weakness, lethargy and even incontinence due to decreased neuronal, neuromuscular and skeletal muscle excitation1,2,3. Satisfied that “Sadie’s” hypercalemic state could explain the majority of her clinical signs, the focus of the clinical investigation shifted to determining which differential for 5 hypercalcemia was most likely in a 10 year old, spayed female, mixed-breed dog. Again, “Sadie’s” owners reported no possible exposure to cholecalciferol-containing rodenticides or poisonous plants, making vitamin D toxicosis less likely. Additionally, her owners were not supplementing her with exogenous vitamin D or calcium. Finally, low serum phosphorus levels are not consistent with hypervitaminosis D. Renal secondary hyperparathyroidism caused by chronic renal failure was less likely based on blood urea nitrogen (BUN) and creatinine levels that were within normal limits and a low-normal serum phosphorus value. Classically, dogs with chronic renal failure have markedly elevated serum phosphorus levels. However, without a urine specific gravity measurement, renal failure could not be ruled-out. Classically, dogs with hypoadrenocorticism or Addison’s disease will present with a hyperkalemia, hyponatremia, and a NA/K ration of less than 27:1. Occasionally, Addisonians may develop a reverse stress leukogram characterized by an eosinophilia and lymphocytosis. Additionally, dogs with Addison’s disease are only mildly hypercalcemic. “Sadie-Mae’s” blood work did not reflect these changes. In fact, her leukogram was completely within normal limits, making an inflammatory or granulomatous cause less likely as well. However, her preliminary diagnostic test could not rule-out hypercalcemia of malignancy or primary hyperparathyroidism. To properly work-up a case of hypercalcemia, several diagnostic tests and procedures are required. In addition to the afore mentioned CBC and serum chemistry panel, an urinalysis, abdominal ultrasound, thoracic radiography, ACTH stimulation test, vitamin D levels and a parathyroid panel may also be indicated. Urinalyses provide information about the kidneys ability to concentrate urine and the urine sediment often indicates the presence of crystals in the urine. An abdominal ultrasound allows the clinician to visually evaluate the kidneys and adrenal glands and to look for sites of primary or metastatic neoplasia. Thoracic radiographs may be helpful in identifying mediastinal neoplasia, pulmonary metastases, or granulomatous diseases such as systemic mycosis. An ACTH stimulation test would help to rule-out the possibility of 6 hypoadrenocorticism. Obviously, elevated serum vitamin D levels would suggest exogenous supplementation of some type. A parathyroid panel ideally includes measurements of the patient’s total calcium, ionized calcium, phosphorus, intact parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP) levels. When attempting to differentiate between hypercalcemia of malignancy and primary hyperparathyroidism, it is best to focus on both the intact PTH and PTHrP levels as both malignancy and primary parathyroid disease cause elevated total and ionized calcium. Phosphorus levels can be normal to low-normal in either disease. However, in the classic examples of hypercalcemia of malignancy (T-cell lymphoma, apocrine adenocarcinoma of the anal sac) PTH levels are low while PTHrP levels are quite elevated. With that said, there are neoplastic processes (multiple myeloma, mammary and thyroid carcinomas) that cause hypercalcemia without elevated PTHrP levels, however in those situations the PTH levels are still low. In primary hyperparathyroidism, the hypercalcemia is caused by functional hyperplastic or neoplastic chief cells that produce too much PTH. The parathyroid panel of a dog with primary hyperparathyroidism is characterized by a normal to elevated PTH level and normal PTHrP level (see Appendix A). “Sadie-Mae’s” parathyroid panel revealed a markedly elevated ionized calcium level (2.31 mmol/L; reference range, 1.25 to 1.45 mmol/L), a mildly elevated PTH level (14.7 pmol/L; reference range, 2 to 13 pmol/L) and a PTHrP level that was within normal limits (0.7 pmol/L; reference range, <1.0 pmol/L). Based on these results a diagnosis of primary hyperparathyroidism was made. It is worth noting that, even if her PTH level was within normal limits, a diagnosis of primary hyperparathyroidism would still made. The reason for this, all other causes of hypercalcemia, regardless of etiology, result in a PTH level at or near zero due to negative feedback on the parathyroid glands by the elevated ionized calcium. Primary hyperparathyroidism is a disease of middle-aged to older dogs (mean=10.5 years; range 5-15 years)3. It has no gender predilection, however certain breeds are predisposed3. 7 Breeds at greatest risk of developing primary hyperparathyroidism are the Keeshond, German Shepard, Poodle, Golden Retriever, Labrador Retriever, Doberman Pinscher, and Cocker Spaniel3. As mentioned previously, it is caused by functional hyperplastic or neoplastic chief cells that produce too much PTH. Excessive PTH sectretion causes increased calcium resorption from bone and reabsorption in the kidney (see Appendix B). Typically, dogs develop a single, solitary functional parathyroid adenoma3,4. Far less common causes include parathyroid gland carcinoma and hyperplasia. When parathyroid gland hyperplasia does occur, it typically affects all four glands2. With a presumptive diagnosis of primary hyperparathyroidism, a cervical ultrasound was performed to confirm the presence of hyperplastic or neoplastic parathyroid tissue. Cervical ultrasound confirmed the diagnosis, revealing a small, focal (5x3.5 mm), round-oval, hypoechoic nodule located in the thyroid tissue on the right side. This finding was consistent with a solitary functional parathyroid adenoma. Based on this result, “Sadie-Mae’s” owners opted to pursue therapy. Immediate medical management of hypercalcemia is the same regardless of the underlying etiology. Hypercalcemic patients are typically diuresed with 0.9% NaCl solution. NaCl is chosen over other crystalloid solutions because sodium competes with calcium for reabsorption in the renal tubules, promoting calciuresis. If 0.9% NaCl is not available, other balanced electrolyte solutions will suffice in that crystalloids will volume expand the patient, increase GFR and increase the filtered load of calcium. In addition to using 0.9% NaCl to diurese the patient, some clinicians opt to promote further calciuresis by giving furosemide (0.5mg/kg) 1. Furosemide, by blocking the Na/K/2Cl pumps in the ascending Loop of Henle, promote calcium excretion by increasing the tubular concentration of sodium. In emergency situations where electrolyte abnormalities must be corrected quickly, sodium bicarbonate therapy (1-4 mEq/kg) can be important1. Giving bicarbonate raises the blood pH, drives hydrogen ions off of serum proteins such as albumin, and allows ionized calcium to 8 bind. This rapidly lowers the ionized calcium levels and corrects life-threatening hypercalcemic states. Glucocorticoids have long been known to lower serum calcium levels. Humans on chronic corticosteroid therapy may develop osteoporosis due in part to decreases in intestinal absorption and decreased renal reabsorption of calcium. Additionally, glucocorticoids tend to decrease bone resorption, promoting a hypocalcemic state. In cases of malignancy, where the hypercalcemia is caused by PTHrP producing T-cell lymphoma, glucocorticoids, through their selective cytotoxicity toward neoplastic lymphocytes, may decrease serum calcium concentrations quite dramatically. Exogenous calcitonin (4 IU/kg IV) can be given to rapidly reduce serum calcium levels1. Calcitonin works by decreasing osteoclastic bone resorptive activity, thereby decreasing the amount of calcium liberated from bone. Another related therapy is the use of bisphosphonates. Bisphosphonates, similar to calcitonin, decrease osteoclastic activity and function. In a last-ditch effort to rescue a profoundly hypercalcemic patients, calcium chelation therapy can be employed using EDTA (25-75 mg/kg/hr IV) 1. Finally, hemodialysis or peritoneal dialysis with calciumfree dialysate can reduce serum calcium levels quickly in a crisis situation. Medical management is extremely important to rapidly correct life-threatening hypercalcemic states and as part of the supportive care necessary while awaiting a definitive diagnosis and therapy. However, medical management has limited usefulness as a long-term therapy option and does not address the underlying etiology. Cases of primary hyperparathyroidism, while they may have been stabilized medically, are traditionally treated surgically. Parathyroidectomies are quite beneficial in that they provide the surgeon with a thorough cervical exploration of the structures in the ventral neck. Additionally, the parathyroidectomy procedure allows for complete excision of the affected gland(s) and collection of tissue for histopathology. However, parathyroidectomies have been associated with profound postoperative hypocalcemic episodes2. Additionally, due to the precarious location of the 9 parathyroid glands, there is a risk of damage to adjacent structure such as the carotid artery, recurrent laryngeal nerve, thyroid tissue, etc. Finally, as is true with virtually any surgical procedure, the parathyroidectomy is associated with a certain amount of postoperative morbidity. In recent years, a new alternative has evolved for the treatment of primary hyperparathyroidism. Percutaneous ethanol inject (PEI) employs a bolus of 96% ethanol injected directly into the discreet nodule of the affected parathyroid gland using ultrasound guidance. The ethanol causes vascular thrombosis within the parathyroid parenchyma and coagulation necrosis of the neoplastic or hyperplastic chief cells5. Prior to being adopted by veterinary medicine, PEI was used successfully in human medicine to ablate small benign masses in the parathyroid, thyroid and liver6,7,8. Most recently it has also been used to treat cats with hyperthyroidism9,10. The materials required to perform PEI correctly include: a 27 gauge needle, extension tubing, 1 cc syringe, 96% ethanol, and most importantly a high quality ultrasound unit (10 MHz). The procedure is generally performed under light anesthesia using a fast-acting injectable anesthetic such as Propofol (3-5 mg/kg IV). The injection site is clipped and sterilely prepped similar to the surgical field of a parathyroidectomy. The discreet parathyroid nodule can then be visualized using the ultrasound probe. Once visualized, the nodule can be injected with ½ to 1 times the estimated mass volume or the operator can simply watch for visual evidence of complete infiltration. Mass volume is defined as the product of the length x width x height of the nodule measured ultrasonographicly. As is true for the parathyroidectomy procedure, care must be taken to avoid vital structures that reside adjacent to the parathyroid glands. However, retrograde leakage of ethanol out of the thyroid gland and into the surrounding thyroid tissue has been shown to have no effect on thyroid function11. In the hands of an experienced operator, the entire procedure may take only 15 minutes to perform. Based on the fact that this procedure had only be attempted on one other occasion at the Cornell University Hospital for Animals (CUHA), a typical general anesthetic protocol was used rather than an injectable anesthetic. “Sadie-Mae” was premedicated with Butorphanol and 10 Midazolam (0.2 mg/kg), induced with Propofol (2.5 mg/kg) and maintained on inhalant Isoflurane. A small, focal (5x3.5 mm), round-oval, hypoechoic parathyroid nodule was easily visualized on the right side of her neck using a 10 MHz ultrasound probe. The nodule was injected with 0.6cc of 96% EtOH and the patient recovered quickly and without complications. The procedure does not end with the injection. Post-procedural monitoring is as important as the injection itself. Ideally, the patient should remain in the hospital for 5-7 after the procedure. A thorough physical exam should be performed twice per day. The injection site should be inspected for signs of inflammation. If possible, a follow-up cervical ultrasound should be performed approximately 5 days and then again at 30 days post-procedure to monitor mass regression. The patient’s serum calcium levels should also be tracked for approximately 5-7 days. Ideally, both the total calcium and the ionized calcium would be measured twice per day for a week and then at regular weekly to monthly intervals. Finally, the patient would be watched very carefully for any signs of hypocalcemia. Post-procedural hypocalcemia is due to the atrophied glands inability to secrete proper amounts of PTH due to prolonged negative feedback suppression from the autonomously functioning hyperplastic or neoplastic gland(s) 2. The duration and severity of the post-procedural hypocalcemic episode has been linked to the duration and severity of the hypercalcemia prior to therapy11. Signs of hypocalcemia include: facial pruritis, muscle tremors/fasciculations, a stiff gait, restlessness, excitation, tachycardia, panting and pyrexia1,3. Within two days of her injection, “Sadie-Mae’s” total and ionized calcium concentrations were within the normal reference range (Figs. 1&2). Serum calcium levels typically decrease to normal or subnormal values within 2-5 days of PEI therapy5,12. As illustrated in Figure 1, “Sadie’s” total calcium normalized on Day 2 and remained within the normal range for the remainder of her hospitalization. Her ionized calcium dipped below the normal limits two times, once on Day 3 and again on Day 5 (Fig. 2). 11 18 90 90 2.5 80 12.8 80 16 70 14 TC a (mg/dL) 60 12 50 10 408 30 20 10 6 4 2 0 iCa (m m ol/L) 70 2 60 East West 7.2 North 1.5 50 40 30 10 1 East 1.12 West North 1.40 20 0.5 00 1st D 1 D 3rd Qtr4th Qtr D 0Qtray2nd ay 2 D 3 D 4 D 5 D 6 ay ay ay ay ay Qtr 0 1st 2nd 3rd Day 0 Day 1 Day 2 Qtr Qtr Qtr 4th Day 4 Qtr Day 5 Day 6 Figure 1. Figure 2. By the morning of Day 3, “Sadie-Mae” had begun to scratch and rub her muzzle on the cage bars. She was also noticed to have a stiff, slightly ataxic gait. She was immediately started on injectable calcium gluconate therapy (50 mg/kg SQ TID). By that evening she had increased energy levels, no signs of stiffness or ataxia and her pruritis had abated. On Day 4, “Sadie” had only mild trembling in the hind limbs when she postured to urinate. The decision was made to switch her to oral calcium supplementation and begin vitamin D therapy. It is more efficacious to give vitamin D along with the oral calcium supplementation as vitamin D tends to increase calcium absorption from the gut. On Day 4, “Sadie” was started on extra strength Tums (50mg/kg PO BID) and Dihydrotachysterol (DHT) (0.01 mg/kg PO SID). On Day 5, “Sadie” again had a slightly stiff gait, tended to frequently shift her weight between her hind limbs and was mildly weak in the hindend. As a precaution she was given another injection of calcium gluconate (50 mg/kg SQ) and monitored carefully. By Day 6, she had again regained her strength and her trembling ceased. She continued to improve throughout the day and into the next. She was subsequently discharged to the care of her owners seven days after her injection. Throughout the month following therapy, “Sadie-Mae” remained energetic and normocalcemic. Since that time the patient has been lost to follow-up. It is the opinion of this author that the signs of hypocalcemia that recurred on Day 5 12 were the result of discontinuation of the parenteral calcium gluconate therapy in conjunction with the lag time associated with the slower acting oral calcium and vitamin D therapy. Upon being discharged from the hospital, “Sadie-Mae’s” owners were instructed to continue oral calcium and vitamin D supplementation at the dosages mentioned above for 2 weeks. They were instructed to monitor her total calcium concentrations at their local veterinarian on weekly basis. Based on those results, the local veterinarian would begin to taper the doses of calcium and vitamin D as he saw fit. Her owners were instructed to watch carefully for signs of hypocalcemia and if any signs occurred they were to rush “Sadie” to their veterinarian immediately for a calcium injection. They were also instructed to monitor for stranguria, as radiographs done while at Cornell indicated the presence of calculi, presumably calcium-oxalate uroliths, in the urinary bladder. They were also encouraged to pursue a cystotomy procedure to remove the cystic calculi before an urinary obstruction occurred. Finally, they were warned that this procedure has an approximately 90% success rate and that “Sadie-Mae” may be amongst the 10% of dogs that need an additional injection or may need to have a parathyroidectomy11. In addition to the possible need for repeat injections, there are a few minor drawback to PEI therapy. Similar to parathyroidectomies, PEI therapy can result in a transient post-procedural hypocalcemia, usually occurring 2-5 days after the injection12. Local inflammation at the injection site is possible but is rarely seen7. Some owners report a transient mild change in their dogs bark, due likely to irritation of the recurrent laryngeal nerve5. Finally, the procedure is technically challenging especially for clinicians not accustom to imaging the ventral cervical region and it does require a high quality ultrasound unit. However, the benefits of PEI therapy are numerous. It can be employed in both the university and private practice setting. Parathyroid PEI does not effect thyroid function. This modality is extremely efficient in that multiple nodules can be injected at once. If the therapy fails, surgery is still a viable option. Calcium levels tend to normalize quickly (2-5 days) and require less post-therapy supportive care. Finally, there is less post-procedural morbidity 13 associated with an inject than there is with general surgery. In conclusion, Ultrasound-guided percutaneous ethanol injection is a safe, viable, efficacious alternative to parathyroidectomy for the treatment of primary hyperparathyroidism in most dogs. 14 References: 1. DiBartola SP. Fluid Therapy in Small Animal Practice. Philadelphia: WB Saunders Co. 2000; 175-186. 2. Flanders JA. Parathyroid Glands. In: Slatter D. Textbook of Small Animal Surgery. Philadelphia: WB Saunders Co, 1993; 1523-1536. 3. Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction. Philadelphia: WB Saunders Co. 1996; 455-496. 4. Berger B, Feldman EC. Primary hyperparathyroidism in dogs: 21 cases (1976-1986). J Am Vet Med Assoc 1987;191:350. 5. Long CD, Goldstein RE, Hornof WJ et al. Percutaneous ultrasound-guided chemical parathyroid ablation for treatment of primary hyperparathyroidism in dogs. J Am Vet Med Assoc 1999;215(2):217-220. 6. Monazi F, Caraccio N, Goletti O, et al. Five-year follow-up of percutaneous ethanol injection for the treatment of hyperfunctioning thyroid nodules: a study of 117 patients. Clin Endocrinol 1997;81:3261-3264. 7. Karstrup S, Hegedus L, Holm H, et al. Ultrasonically guided chemical parathyroidectomy in patients with primary hyperparathyroidism: a follow-up study. Clin Endocrinol 1993;38:523530. 8. Livraghi T, Festi D, Monti F, et al. Ultrasound guided percutaneous alcohol injection of small hepatic and abdominal tumors. Radiology 1986;161:309-312. 9. Wells AL, Long CD, Hornof WJ et al. Use of percutaneous ethanol injection for treatment of bilateral hyperplastic thyroid nodules in cats. J Am Vet Med Assoc 2001;218(8):1293-1297. 10. Goldstein RE, Long CD, Swift NC et al. Percutaneous ethanol injection for treatment of unilateral hyperplastic thyroid nodules in cats. J Am Vet Med Assoc 2001;218(8):1298-1301. 11. Goldstein RE. Personal communication 12. Goldstein RE, Kantrowitz B, Long CD et al. Ultrasound guided percutaneous ethanol injection (PEI) for the treatment of primary hyperparathyroidism in 17 dogs. Abstract: Proceeding of ECVIM Congress 2000. 15 Appendix A TCa iCa Phos PTH PTHrP Malignancy N N N N N N PHPT Addison's Granuloma CRF Hypervit D 16 Appendix B Flanders JA. Parathyroid Glands. In: Slatter D. Textbook of Small Animal Surgery. Philadelphia: WB Saunders Co, 1993; 1523-1536. 17