Veterinary Quarterly, 2013 Vol. 33, No. 4, 195–200, http://dx.doi.org/10.1080/01652176.2013.864429
CASE REPORT Primary hyperparathyroidism with chronic renal failure in a Vietnamese pot-bellied pig (Sus scrofa) S.E. Dumasa,y*, T.M. Grandysa, A.W. Sternb, E.F. Garretta and M.D. Ridgwayc a Rural Animal Health Management, University of Illinois, 1008 W Hazelwood Ave, Urbana, IL 61802, USA; bVeterinary Diagnostic Laboratory, University of Illinois, 2001 S Lincoln Ave, Urbana, IL 61802, USA; cCompanion and Zoo Animal Medicine, University of Illinois, 1008 W Hazelwood Ave, Urbana, IL 61802, USA
(Received 28 August 2013; accepted 6 November 2013) Keywords: pig; porcine; Sus scrofa; renal failure; hyperparathyroidism; PTH; PU/PD; Trueperella pyogenes
Abbreviations: CRD chronic renal disease MAP mean arterial pressure PHPT primary hyperparathyroidism PTH parathyroid hormone PTHrP parathyroid hormone-related protein PU/PD polyuria/polydipsia
A 14-year-old spayed female Vietnamese pot-bellied pig was presented to the University of Illinois Veterinary Teaching Hospital with a complaint of lethargy, anorexia, polyuria/polydipsia (PU/PD), and dyspnea. Three years prior to presentation, the owner had noted a white, granular material expressed at the end of urination, which left a chalky residue on the vulva. In-house urinalysis at that time showed the presence of calcium oxalate crystals. Six months later, the patient was diagnosed with presumptive osteoarthritis in multiple joints. She was treated with carprofen 150–200 mg orally twice daily, which was increased to 300 mg twice daily at times of severe lameness, and this regimen had been followed continuously since that time. For several years prior to presentation, the owner was feeding a commercial diet formulated for geriatric Vietnamese pot-bellied pigs,1 plus supplemental feed of fruits and vegetables. Two years before presentation, the owner had reported increased drinking and frequency of urination. One year prior to presentation, the owner noted dyspnea and stridor; worsening of these respiratory signs prompted presentation. At presentation, the patient was quiet, alert, responsive, and sternally recumbent. She was moderately overconditioned, weighing 83.2 kg with a body condition score of 6 out of 9. On physical examination, her vital signs were within normal limits (temperature 37.7 C, heart rate 160 beats per minute, respiratory rate 40 breaths per minute and euhydrated). She was able but reluctant to stand. Auscultation of the heart and lungs was
complicated by referred upper-respiratory sounds. However, the pig displayed no outward evidence of dyspnea. Blood was collected for a complete blood count and biochemistry. No reference ranges are available for Vietnamese pot-bellied pigs in our laboratory, but general guidelines for normal are available online from the Merck Veterinary Manual (2013). The tests revealed azotemia (creatinine ¼ 397.8 mmol/L, normal ¼ 35–97; blood urea nitrogen (BUN) ¼ 17.1 mmol/L, normal ¼ 3.9–17), severe hypercalcemia (total Ca ¼ 4.2 mmol/L, normal ¼ 2.5–3.1; ionized Ca ¼ 1.7 mmol/L, normal ¼ 1.0–1.4) with normophosphatemia (1.8 mmol/L, normal ¼ 1.6– 3.4), elevated gamma-glutamyl transpeptidase (GGT) activity (120 U/L, normal ¼ 21–57), possible hypercholesterolemia (5.6 mmol/L, no normal values available, but higher than that expected for other domestic species), and a normochromic, normocytic anemia (hematocrit ¼ 0.22 L/L, normal ¼ 0.37–0.51) that was likely non-regenerative based on cytology. The white blood cell (WBC) count was within the broad published normal ranges, but was notably increased compared to her previous values in the years leading up to presentation (WBC ¼ 25.5 109/L, neutrophils ¼ 21.4 109/L (Table 1). Urinalysis of a free-catch sample showed isosthenuria (refractometer urine specific gravity [USG] ¼ 1.008), with proteinuria (1.0 g/L) and glycosuria (13.9 mmol/L). A few calcium oxalate crystals were found. A urine culture was not performed due to difficulty in obtaining a sample by cystocentesis. Review of the patient’s previous laboratory results showed the presence of hyposthenuria and progressively worsening azotemia beginning 10 months prior to presentation (Table 1). The progressive azotemia with concurrent isosthenuria and the two-year history of PU/PD prompted a diagnosis of chronic renal disease (CRD), although the persistent hypercalcemia also likely contributed to PU/PD. The patient’s normochromic, normocytic, non-regenerative anemia was consistent with the anemia of CRD. An indirect blood pressure measurement
*Corresponding author. Email: [email protected] y Current address: Cornell University, College of Veterinary Medicine, Office of Graduate Education, Schurman Hall, S3-016, Box 38, Ithaca, New York 14853-6401, USA. Ó 2013 Taylor & Francis
196
S.E. Dumas et al.
Table 1. Tracking of azotemia, hyposthenuria, hypercalcemia, anemia, and leukocytosis in a 14-year-old spayed female Vietnamese pot-bellied pig over time.
Creatinine (mmol/L) BUN (mmol/L) USG Total calcium (mmol/L) Phosphorus (mmol/L) Albumin (g/L) Hematocrit (L/L) WBC (109/L) Neutrophils (109/L)
14 May 2008
25 May 2010
6 Oct 2011
30 Mar 2012
21 Aug 2012
Normal range
76.3 3.8 – 2.5 1.8 45 0.327 15.5 10.9
106.8 2.0 – 3.1 1.0 47 – – –
91.5 2.1 1.003 3.5 1.2 40 0.404 14.8 9.3
167.8 4.3 – 3.6 0.8 37 0.351 17.1 8.9
358.4 18.9 1.008 4.2 1.8 41 0.22 25.5 21.4
35–97 3.9–17 1.010–1.050 2.5–3.1 1.6–3.4 31–43 0.37–0.51 19–38 3.3–24
documented severe hypertension (246/129, mean arterial pressure [MAP] 206 mm Hg). The patient was started on an angiotensin-converting enzyme (ACE) inhibitor (enalapril 0.5 mg/kg body weight (BW) orally twice daily) and a calcium channel blocker (amlodipine 0.1 mg/kg BW orally once daily). Her blood pressure after initiation of therapy averaged 145/87 (MAP 113) mm Hg and remained stable for the duration of her hospital stay. An ophthalmologic examination showed no evidence of hypertensive retinopathy. Review of historical biochemistry results showed progressive hypercalcemia beginning two years prior to presentation. Phosphorus levels were consistently low to low-normal during that time period (Table 1), consistent with excess parathyroid hormone (PTH) or parathyroid hormone-related protein (PTHrP) activity. Given the magnitude of hypercalcemia and the patient’s advanced age, underlying malignancy with paraneoplastic hypercalcemia was considered. Tests for PTH and PTHrP were submitted.2 Three-view thoracic radiographs were obtained
under sedation, which demonstrated a soft-tissue opacity measuring 2.9 cm in diameter in the right caudal thorax. An ultrasound-guided fine-needle aspirate of the mass was attempted, but a diagnostic sample could not be obtained. No other abnormalities of the thorax were noted, and no evidence of loss of bone density was noted on the long bones or axial skeleton. On abdominal ultrasound examination, the left and right kidneys measured 10.6 cm in length with indistinct corticomedullary junctions bilaterally (Figure 1). The abdominal ultrasound was otherwise unremarkable. The patient remained in the hospital for seven days for treatment of CRD, hypertension, and hypercalcemia with intravenous fluid therapy, oral nutrition, antihypertensives, and gastroprotectants (sucralfate 1 g three times daily and omeprazole 0.5 mg/kg BW orally once daily). The carprofen was discontinued due to the risk of renal toxicity. Because of the patient’s continued reluctance to stand, treatment with tramadol (2 mg/kg BW twice daily) and a short course of prednisone (1 mg/kg BW orally
Figure 1. Ultrasonographic image of the right kidney. Note the decreased corticomedullary junction.
Veterinary Quarterly
197
Figure 2. Postmortem gross image of the kidney. Note the variation in cortical thickness, indistinct corticomedullary junction, and cystic dilations within the cortex.
initially, then tapered and discontinued) was initiated for control of pain and inflammation associated with osteoarthritis. Despite the increased risk of gastric ulcers associated with CRD and the use of corticosteroids in the face of recent non-steroidal anti-inflammatory drug use (Rainsford et al. 2003), prednisone therapy was deemed necessary to maintain an acceptable quality of life. Gastroprotectants and appropriate fluid therapy were employed to minimize risks of gastric ulceration (Stapleton et al. 1989). The patient responded partially to the therapy, with improved appetite and normalization of her blood pressure. No evidence of dyspnea was observed during her
hospital stay, though occasional episodes of stertor were noted during sleep. She was discharged after seven days but returned two days later for euthanasia due to worsening clinical condition. At necropsy, gross examination of the kidneys showed bilateral, diffuse fibrosis with multifocal cystic dilations within the cortex (Figure 2). Both external parathyroid glands were pale and enlarged bilaterally, measuring 10 6 6 mm. (It should be noted that pigs normally have only a single pair of parathyroid glands.) Histopathology showed extensive effacement of renal structures by fibrous tissue, with thickening of the few remaining glomeruli and poorly defined capillaries
Figure 3. Histopathology of the kidney. Extensive interstitial fibrosis, scattered lymphocyte aggregates within the interstitium and renal tubule dilation.
198
S.E. Dumas et al.
Figure 4. Histopathology of the parathyroid gland. The gland is markedly expanded by multifocal hyperplastic nodules with no atypical cells.
(Figure 3). Approximately 50% of cortical tubules were lost, with the remaining tubules distorted by fibrosis. There was scattered flattening of the tubular epithelium suggestive of renal tubular damage and cystic dilation of multiple renal tubules, and many tubules contained amorphous to fibrillar, pale eosinophilic material (protein) and smooth, glassy, homogeneous, bright eosinophilic material (hyaline casts). Multifocal pockets of inflammatory cells consisting of lymphocytes, plasma cells, neutrophils, and eosinophils were present within tubules and interstitium. Renal calcification was not evident. Histopathology showed the parathyroid glands to be markedly expanded by multiple hyperplastic nodules (Figure 4). Chief cells within the nodules are packed together and have a uniform composition with a high cytoplasm to nucleus ratio. A peripheral rim of compressed parathyroid parenchyma was not observed. These postmortem findings are consistent with the clinical diagnosis of chronic renal disease and hyperparathyroidism. Other postmortem findings included a 2 2 2 cm pulmonary abscess cultured as Trueperella pyogenes in the right caudal lobe, consistent with the radiographic findings of a soft-tissue opacity in the right caudal thorax, osteoarthritis, mild gastritis and enteritis, gallbladder mucosal polyps, and mild interstitial pancreatitis. Examination of the spleen showed mild extramedullary hematopoiesis consistent with chronic anemia. There was no histological evidence of metastatic mineralization and no gross evidence of fibrous osteodystrophy. On gross examination the breaking strength of bone (ribs) was not noticeably reduced; bone histopathology was not performed. The results of the PTH and PTHrP assays, received after the patient was euthanized, showed markedly elevated PTH concentration (45.1 pmol/L) with normal PTHrP (0.0 pmol/L). Although the laboratory does not
maintain reference values for pigs or pot-bellied pigs, the PTH result was markedly elevated relative to levels in all species for which the laboratory has data (dog 0.5–5.8 pmol/L, cat 0.4–2.5 pmol/L, horse 0.6–11 pmol/L, and human 0.6–3.4 pmol/L). In this report we describe a case of concurrent hyperparathyroidism and CRD in a geriatric Vietnamese potbellied pig. The findings of both conditions create a difficult diagnostic scenario, because hypercalcemia can either cause secondary CRD or occur as a consequence of primary renal disease. Alternatively, each condition may have occurred independently. However, careful review of the historical laboratory data strongly suggests primary hyperparathyroidism (PHPT) with later development of CRD. Nutritional secondary hyperparathyroidism was not considered as a differential diagnosis, because the pig was maintained on a commercial diet, showed no evidence of malabsorptive intestinal disease or loss of bone density, and had an extremely elevated ionized calcium. PHPT is a disorder in which one or more parathyroid glands are overactive and unresponsive to normal negative feedback mechanisms, releasing excess PTH and resulting in hypercalcemia and hypophosphatemia. Clinical signs include PU/PD, urinary incontinence, dysuria, cystic calculi, weakness, lethargy, muscle wasting, inappetence, vomiting, and constipation. Chronic osteoclast stimulation by elevated PTH may result in fibrous osteodystrophy; facial hyperostosis, thinning of the bones of the skull and jaw, and tooth loss are also reported (Feldman 2010). In both dogs and humans, PHPT is generally caused by a single functional parathyroid adenoma (Berger & Feldman 1987; Schenck et al. 2012). However, approximately 15% of PHPT cases in humans are caused by chief cell hyperplasia, defined as the proliferation of chief cells
Veterinary Quarterly leading to an increase in the size of multiple parathyroid glands in the absence of a known stimulus for PTH (Ghandur-Mnaymneh & Kimura 1984; Baloch & LiVolsi 2004). Primary parathyroid gland hyperplasia has also been reported in dogs, typically affecting a single gland, though there are several reports of multiple glands being affected (Krook 1957; Peterson et al. 1982; DeVries et al. 1993; van Vonderen et al. 2003). The clinical presentation is indistinguishable from that of solitary parathyroid adenoma. PU and PD are commonly reported in cases of PHPT in humans and dogs (Kruger et al. 1996; Rijnberk & Hazewinkel 1996; van Vonderen et al. 2003; Schenck et al. 2012), likely due to a combination of functional and structural effects of hypercalcemia on the kidneys. First, there is evidence that hypercalcemia causes reduced tubular reabsorption of sodium and impaired renal response to antidiuretic hormone, resulting in a reversible nephrogenic diabetes insipidus (Baylis et al. 1981; Garofeanu et al. 2005). Second, experimental hypercalcemia has been shown to induce increased renal medullary blood flow, resulting in a loss of the medullary interstitial tonicity and subsequent loss of urine concentrating ability (Garofeanu et al. 2005). Third, hypercalcemia induces renal vasoconstriction, resulting in decreased renal blood flow, which can result in renal ischemia, tubular dysfunction, and tubular and interstitial fibrosis over time (Schenck et al. 2012). Finally, hypercalcemia can cause mineralization of the renal tubules or interstitium (Kruger et al. 1996; Baloch & LiVolsi 2004). There is a high prevalence of CRD in geriatric animals of all domestic species, though it is only anecdotally reported in pot-bellied pigs. In response to renal injury, the initial adaptive response of the kidney is hypertrophy of the remaining nephrons to maintain glomerular filtration rate. Angiotensin II, local prostaglandins, and nitric oxide mediate preferential vasodilation of the afferent arterioles, promoting glomerular hypertension and hyperfiltration. According to the hyperfiltration theory, this leads to glomerular endothelial damage and increased protein flux, with resulting glomerular sclerosis and nephron loss. As an increasing number of nephrons are lost, total renal function becomes increasingly impaired (Brenner et al. 1996; Polzin 2010). Serum calcium levels in patients with CRD are typically normal or low due to decreased calcitriol synthesis in the kidney, which results in reduced intestinal and renal calcium absorption and reduced negative feedback on the parathyroid. This reduction in negative feedback, combined with parathyroid stimulation by elevated phosphorus levels, triggers parathyroid hyperplasia (Polzin 2010). Subsequent autonomous hypersecretion of PTH is termed renal secondary hyperparathyroidism. Rarely, patients with chronic secondary hyperparathyroidism progress to tertiary hyperparathyroidism, in which nodular hyperplasia leads to PTH hypersecretion that is not suppressed by elevated ionized Ca (Mac Way et al. 2012). Clinically, this is manifested as hypercalcemia and very high serum PTH concentration.
199
It is plausible, then, that the patient described in this report suffered from primary, idiopathic CRD, which resulted in secondary hyperparathyroidism and, ultimately, tertiary hyperparathyroidism. However, examination of serial blood work leading up to her presentation shows that this patient never demonstrated hypocalcemia or hyperphosphatemia, as would be expected had she experienced a period of renal or nutritional secondary hyperparathyroidism. In fact, phosphorus levels remained normal or below normal during that time, while total Ca started within the reference range before trending upward. Furthermore, the patient’s creatinine and BUN remained low or normal until March 2012 and August 2012, respectively, while hypercalcemia and isosthenuria were first documented in May 2010 and October 2011, respectively. This suggests that the patient’s clinical signs were likely the result of PHPT with the later development of CRD. However, the exact relationship between the patient’s CRD and PHPT remains unclear. The clinical, gross, and histological findings in the case reported here are consistent with primary multinodular parathyroid gland hyperplasia, leading to the excessive, unregulated excretion of PTH and resultant hypercalcemia and mild hypophosphatemia. The chronic hypercalcemia may have caused or contributed to the development of CRD by driving chronic hyperfiltration, renal vasoconstriction, and subsequent glomerular sclerosis and nephron loss (Brenner et al. 1996). Alternatively, the patient may have experienced concurrent, independently occurring PHPT and primary CRD. Although CRD is anecdotally described as a disease encountered in geriatric pot-bellied pigs, to the authors’ knowledge, this is the first report of either PHPT or chronic renal failure in a Vietnamese pot-bellied pig.
Acknowledgements The authors would like to thank the pig’s owner for their dedication. The authors would also like to thank the radiologists, clinical pathologists, and staff at the University of Illinois Veterinary Teaching Hospital for their excellent patient care.
Notes 1. 2.
Mazuri Mini Pig Elder. PTH and PTHrP assays performed at the Diagnostic Center for Population and Animal Health at Michigan State University, East Lansing, USA.
References Baloch ZW, LiVolsi VA. 2004. Parathyroid glands. In: Martini L, editor. Encyclopedia of endocrine diseases. New York (NY): Elsevier; p. 505–512. Baylis PH, Milles JJ, Wilkinson R, Heath DA. 1981. Vasopressin function in hypercalcaemia. Clin Endocrinol. 15:343–351. Berger B, Feldman EC. 1987. Primary hyperparathyroidism in dogs: 21 cases (1976–1986). J Am Vet Med Assoc. 191:350–356. Brenner BM, Lawler EV, Mackenzie HS. 1996. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int. 49:1774–1777.
200
S.E. Dumas et al.
DeVries SE, Feldman EC, Nelson RW, Kennedy PC. 1993. Primary parathyroid gland hyperplasia in dogs: six cases (1982–1991). J Am Vet Med Assoc. 202:1132–1136. Feldman EC. 2010. Disorders of the parathyroid glands. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine. 7th ed. St. Louis (MO): Saunders Elsevier; p. 1722–1751. Garofeanu CG, Weir M, Rosas-Arellano MP. 2005. Causes of reversible nephrogenic diabetes indipidus: a systematic review. Am J Kidney Dis. 45:626–637. Ghandur-Mnaymneh L, Kimura N. 1984. The parathyroid adenoma: a histopathologic definition with a study of 172 cases of primary hyperparathyroidism. Am J Pathol. 115:70–83. Krook L. 1957. Primary hyperparathyroidism in the dog. Acta Pathologica et Microbiologica Scandinavica. 41:27–39. Kruger JM, Osborne CA, Nachreiner RF, Refsal KR. 1996. Hypercalcemia and renal failure: etiology, pathophysiology, diagnosis, and treatment. Vet Clin North Am Small Anim Pract. 26:1417–1445. Mac Way F, Lessard M, Lafage-Proust MH. 2012. Pathophysiology of chronic kidney disease-mineral and bone disorder. Joint Bone Spine. 79:544–549. Merck Veterinary Manual. 2013. Hematological reference ranges and serum biochemistry reference ranges [Internet]. [Cited 2013 Mar 8]. Available from: http://www. merckmanuals.com/vet/appendixes/reference_guides/ hematologic_reference_ranges.html
Peterson ME, Randolph JF, Zaki FA, Heath H. 1982. Multiple endocrine neoplasia in a dog. J Am Vet Med Assoc. 180:1476–1478. Polzin DJ. 2010. Chronic kidney disease. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine. 7th ed. St. Louis (MO): Saunders Elsevier; p. 1990–2021. Rainsford KD, Stetsko PI, Sirko SP, Debski S. 2003. Gastrointestinal mucosal injury following repeated daily oral administration of conventional formulation of indomethacin and other non-steroidal anti-inflammatory drugs to pigs: a model for human gastrointestinal disease. J Pharm Pharmacol. 55:661–668. Rijnberk A, Hazewinkel HAW. 1996. Parathyroids. In: Rijnberk A, editor. Clinical endocrinology of dogs and cats. Dordrecht: Kluwer Academic Publishers; p. 167–176. Schenck PA, Chew DJ, Nagode LA, Rosol TJ. 2012. Disorders of calcium: hypercalcemia and hypocalcemia. In: DiBartola SP, editor. Fluid, electrolyte, and acid-base disorders in small animal practice. 4th ed. St. Louis (MO): Saunders; p. 120–194. Stapleton GN, Marks IN, Fourie AJ, McLeod H, Hickman R, Mall A, Terblanche J. 1989. Sucralfate in the prevention of porcine experimental peptic ulceration. Am J Med. 86:21–22. van Vonderen IK, Kooistra HS, Peeters ME, Rijnberk A, van den Ingh TS. 2003. Parathyroid hormone immunohistochemistry in dogs with primary and secondary hyperparathyroidism: the question of adenoma and primary hyperplasia. J Comp Pathol. 129:61–69.
CASE REPORT Primary hyperparathyroidism with chronic renal failure in a Vietnamese pot-bellied pig (Sus scrofa) S.E. Dumasa,y*, T.M. Grandysa, A.W. Sternb, E.F. Garretta and M.D. Ridgwayc a Rural Animal Health Management, University of Illinois, 1008 W Hazelwood Ave, Urbana, IL 61802, USA; bVeterinary Diagnostic Laboratory, University of Illinois, 2001 S Lincoln Ave, Urbana, IL 61802, USA; cCompanion and Zoo Animal Medicine, University of Illinois, 1008 W Hazelwood Ave, Urbana, IL 61802, USA
(Received 28 August 2013; accepted 6 November 2013) Keywords: pig; porcine; Sus scrofa; renal failure; hyperparathyroidism; PTH; PU/PD; Trueperella pyogenes
Abbreviations: CRD chronic renal disease MAP mean arterial pressure PHPT primary hyperparathyroidism PTH parathyroid hormone PTHrP parathyroid hormone-related protein PU/PD polyuria/polydipsia
A 14-year-old spayed female Vietnamese pot-bellied pig was presented to the University of Illinois Veterinary Teaching Hospital with a complaint of lethargy, anorexia, polyuria/polydipsia (PU/PD), and dyspnea. Three years prior to presentation, the owner had noted a white, granular material expressed at the end of urination, which left a chalky residue on the vulva. In-house urinalysis at that time showed the presence of calcium oxalate crystals. Six months later, the patient was diagnosed with presumptive osteoarthritis in multiple joints. She was treated with carprofen 150–200 mg orally twice daily, which was increased to 300 mg twice daily at times of severe lameness, and this regimen had been followed continuously since that time. For several years prior to presentation, the owner was feeding a commercial diet formulated for geriatric Vietnamese pot-bellied pigs,1 plus supplemental feed of fruits and vegetables. Two years before presentation, the owner had reported increased drinking and frequency of urination. One year prior to presentation, the owner noted dyspnea and stridor; worsening of these respiratory signs prompted presentation. At presentation, the patient was quiet, alert, responsive, and sternally recumbent. She was moderately overconditioned, weighing 83.2 kg with a body condition score of 6 out of 9. On physical examination, her vital signs were within normal limits (temperature 37.7 C, heart rate 160 beats per minute, respiratory rate 40 breaths per minute and euhydrated). She was able but reluctant to stand. Auscultation of the heart and lungs was
complicated by referred upper-respiratory sounds. However, the pig displayed no outward evidence of dyspnea. Blood was collected for a complete blood count and biochemistry. No reference ranges are available for Vietnamese pot-bellied pigs in our laboratory, but general guidelines for normal are available online from the Merck Veterinary Manual (2013). The tests revealed azotemia (creatinine ¼ 397.8 mmol/L, normal ¼ 35–97; blood urea nitrogen (BUN) ¼ 17.1 mmol/L, normal ¼ 3.9–17), severe hypercalcemia (total Ca ¼ 4.2 mmol/L, normal ¼ 2.5–3.1; ionized Ca ¼ 1.7 mmol/L, normal ¼ 1.0–1.4) with normophosphatemia (1.8 mmol/L, normal ¼ 1.6– 3.4), elevated gamma-glutamyl transpeptidase (GGT) activity (120 U/L, normal ¼ 21–57), possible hypercholesterolemia (5.6 mmol/L, no normal values available, but higher than that expected for other domestic species), and a normochromic, normocytic anemia (hematocrit ¼ 0.22 L/L, normal ¼ 0.37–0.51) that was likely non-regenerative based on cytology. The white blood cell (WBC) count was within the broad published normal ranges, but was notably increased compared to her previous values in the years leading up to presentation (WBC ¼ 25.5 109/L, neutrophils ¼ 21.4 109/L (Table 1). Urinalysis of a free-catch sample showed isosthenuria (refractometer urine specific gravity [USG] ¼ 1.008), with proteinuria (1.0 g/L) and glycosuria (13.9 mmol/L). A few calcium oxalate crystals were found. A urine culture was not performed due to difficulty in obtaining a sample by cystocentesis. Review of the patient’s previous laboratory results showed the presence of hyposthenuria and progressively worsening azotemia beginning 10 months prior to presentation (Table 1). The progressive azotemia with concurrent isosthenuria and the two-year history of PU/PD prompted a diagnosis of chronic renal disease (CRD), although the persistent hypercalcemia also likely contributed to PU/PD. The patient’s normochromic, normocytic, non-regenerative anemia was consistent with the anemia of CRD. An indirect blood pressure measurement
*Corresponding author. Email: [email protected] y Current address: Cornell University, College of Veterinary Medicine, Office of Graduate Education, Schurman Hall, S3-016, Box 38, Ithaca, New York 14853-6401, USA. Ó 2013 Taylor & Francis
196
S.E. Dumas et al.
Table 1. Tracking of azotemia, hyposthenuria, hypercalcemia, anemia, and leukocytosis in a 14-year-old spayed female Vietnamese pot-bellied pig over time.
Creatinine (mmol/L) BUN (mmol/L) USG Total calcium (mmol/L) Phosphorus (mmol/L) Albumin (g/L) Hematocrit (L/L) WBC (109/L) Neutrophils (109/L)
14 May 2008
25 May 2010
6 Oct 2011
30 Mar 2012
21 Aug 2012
Normal range
76.3 3.8 – 2.5 1.8 45 0.327 15.5 10.9
106.8 2.0 – 3.1 1.0 47 – – –
91.5 2.1 1.003 3.5 1.2 40 0.404 14.8 9.3
167.8 4.3 – 3.6 0.8 37 0.351 17.1 8.9
358.4 18.9 1.008 4.2 1.8 41 0.22 25.5 21.4
35–97 3.9–17 1.010–1.050 2.5–3.1 1.6–3.4 31–43 0.37–0.51 19–38 3.3–24
documented severe hypertension (246/129, mean arterial pressure [MAP] 206 mm Hg). The patient was started on an angiotensin-converting enzyme (ACE) inhibitor (enalapril 0.5 mg/kg body weight (BW) orally twice daily) and a calcium channel blocker (amlodipine 0.1 mg/kg BW orally once daily). Her blood pressure after initiation of therapy averaged 145/87 (MAP 113) mm Hg and remained stable for the duration of her hospital stay. An ophthalmologic examination showed no evidence of hypertensive retinopathy. Review of historical biochemistry results showed progressive hypercalcemia beginning two years prior to presentation. Phosphorus levels were consistently low to low-normal during that time period (Table 1), consistent with excess parathyroid hormone (PTH) or parathyroid hormone-related protein (PTHrP) activity. Given the magnitude of hypercalcemia and the patient’s advanced age, underlying malignancy with paraneoplastic hypercalcemia was considered. Tests for PTH and PTHrP were submitted.2 Three-view thoracic radiographs were obtained
under sedation, which demonstrated a soft-tissue opacity measuring 2.9 cm in diameter in the right caudal thorax. An ultrasound-guided fine-needle aspirate of the mass was attempted, but a diagnostic sample could not be obtained. No other abnormalities of the thorax were noted, and no evidence of loss of bone density was noted on the long bones or axial skeleton. On abdominal ultrasound examination, the left and right kidneys measured 10.6 cm in length with indistinct corticomedullary junctions bilaterally (Figure 1). The abdominal ultrasound was otherwise unremarkable. The patient remained in the hospital for seven days for treatment of CRD, hypertension, and hypercalcemia with intravenous fluid therapy, oral nutrition, antihypertensives, and gastroprotectants (sucralfate 1 g three times daily and omeprazole 0.5 mg/kg BW orally once daily). The carprofen was discontinued due to the risk of renal toxicity. Because of the patient’s continued reluctance to stand, treatment with tramadol (2 mg/kg BW twice daily) and a short course of prednisone (1 mg/kg BW orally
Figure 1. Ultrasonographic image of the right kidney. Note the decreased corticomedullary junction.
Veterinary Quarterly
197
Figure 2. Postmortem gross image of the kidney. Note the variation in cortical thickness, indistinct corticomedullary junction, and cystic dilations within the cortex.
initially, then tapered and discontinued) was initiated for control of pain and inflammation associated with osteoarthritis. Despite the increased risk of gastric ulcers associated with CRD and the use of corticosteroids in the face of recent non-steroidal anti-inflammatory drug use (Rainsford et al. 2003), prednisone therapy was deemed necessary to maintain an acceptable quality of life. Gastroprotectants and appropriate fluid therapy were employed to minimize risks of gastric ulceration (Stapleton et al. 1989). The patient responded partially to the therapy, with improved appetite and normalization of her blood pressure. No evidence of dyspnea was observed during her
hospital stay, though occasional episodes of stertor were noted during sleep. She was discharged after seven days but returned two days later for euthanasia due to worsening clinical condition. At necropsy, gross examination of the kidneys showed bilateral, diffuse fibrosis with multifocal cystic dilations within the cortex (Figure 2). Both external parathyroid glands were pale and enlarged bilaterally, measuring 10 6 6 mm. (It should be noted that pigs normally have only a single pair of parathyroid glands.) Histopathology showed extensive effacement of renal structures by fibrous tissue, with thickening of the few remaining glomeruli and poorly defined capillaries
Figure 3. Histopathology of the kidney. Extensive interstitial fibrosis, scattered lymphocyte aggregates within the interstitium and renal tubule dilation.
198
S.E. Dumas et al.
Figure 4. Histopathology of the parathyroid gland. The gland is markedly expanded by multifocal hyperplastic nodules with no atypical cells.
(Figure 3). Approximately 50% of cortical tubules were lost, with the remaining tubules distorted by fibrosis. There was scattered flattening of the tubular epithelium suggestive of renal tubular damage and cystic dilation of multiple renal tubules, and many tubules contained amorphous to fibrillar, pale eosinophilic material (protein) and smooth, glassy, homogeneous, bright eosinophilic material (hyaline casts). Multifocal pockets of inflammatory cells consisting of lymphocytes, plasma cells, neutrophils, and eosinophils were present within tubules and interstitium. Renal calcification was not evident. Histopathology showed the parathyroid glands to be markedly expanded by multiple hyperplastic nodules (Figure 4). Chief cells within the nodules are packed together and have a uniform composition with a high cytoplasm to nucleus ratio. A peripheral rim of compressed parathyroid parenchyma was not observed. These postmortem findings are consistent with the clinical diagnosis of chronic renal disease and hyperparathyroidism. Other postmortem findings included a 2 2 2 cm pulmonary abscess cultured as Trueperella pyogenes in the right caudal lobe, consistent with the radiographic findings of a soft-tissue opacity in the right caudal thorax, osteoarthritis, mild gastritis and enteritis, gallbladder mucosal polyps, and mild interstitial pancreatitis. Examination of the spleen showed mild extramedullary hematopoiesis consistent with chronic anemia. There was no histological evidence of metastatic mineralization and no gross evidence of fibrous osteodystrophy. On gross examination the breaking strength of bone (ribs) was not noticeably reduced; bone histopathology was not performed. The results of the PTH and PTHrP assays, received after the patient was euthanized, showed markedly elevated PTH concentration (45.1 pmol/L) with normal PTHrP (0.0 pmol/L). Although the laboratory does not
maintain reference values for pigs or pot-bellied pigs, the PTH result was markedly elevated relative to levels in all species for which the laboratory has data (dog 0.5–5.8 pmol/L, cat 0.4–2.5 pmol/L, horse 0.6–11 pmol/L, and human 0.6–3.4 pmol/L). In this report we describe a case of concurrent hyperparathyroidism and CRD in a geriatric Vietnamese potbellied pig. The findings of both conditions create a difficult diagnostic scenario, because hypercalcemia can either cause secondary CRD or occur as a consequence of primary renal disease. Alternatively, each condition may have occurred independently. However, careful review of the historical laboratory data strongly suggests primary hyperparathyroidism (PHPT) with later development of CRD. Nutritional secondary hyperparathyroidism was not considered as a differential diagnosis, because the pig was maintained on a commercial diet, showed no evidence of malabsorptive intestinal disease or loss of bone density, and had an extremely elevated ionized calcium. PHPT is a disorder in which one or more parathyroid glands are overactive and unresponsive to normal negative feedback mechanisms, releasing excess PTH and resulting in hypercalcemia and hypophosphatemia. Clinical signs include PU/PD, urinary incontinence, dysuria, cystic calculi, weakness, lethargy, muscle wasting, inappetence, vomiting, and constipation. Chronic osteoclast stimulation by elevated PTH may result in fibrous osteodystrophy; facial hyperostosis, thinning of the bones of the skull and jaw, and tooth loss are also reported (Feldman 2010). In both dogs and humans, PHPT is generally caused by a single functional parathyroid adenoma (Berger & Feldman 1987; Schenck et al. 2012). However, approximately 15% of PHPT cases in humans are caused by chief cell hyperplasia, defined as the proliferation of chief cells
Veterinary Quarterly leading to an increase in the size of multiple parathyroid glands in the absence of a known stimulus for PTH (Ghandur-Mnaymneh & Kimura 1984; Baloch & LiVolsi 2004). Primary parathyroid gland hyperplasia has also been reported in dogs, typically affecting a single gland, though there are several reports of multiple glands being affected (Krook 1957; Peterson et al. 1982; DeVries et al. 1993; van Vonderen et al. 2003). The clinical presentation is indistinguishable from that of solitary parathyroid adenoma. PU and PD are commonly reported in cases of PHPT in humans and dogs (Kruger et al. 1996; Rijnberk & Hazewinkel 1996; van Vonderen et al. 2003; Schenck et al. 2012), likely due to a combination of functional and structural effects of hypercalcemia on the kidneys. First, there is evidence that hypercalcemia causes reduced tubular reabsorption of sodium and impaired renal response to antidiuretic hormone, resulting in a reversible nephrogenic diabetes insipidus (Baylis et al. 1981; Garofeanu et al. 2005). Second, experimental hypercalcemia has been shown to induce increased renal medullary blood flow, resulting in a loss of the medullary interstitial tonicity and subsequent loss of urine concentrating ability (Garofeanu et al. 2005). Third, hypercalcemia induces renal vasoconstriction, resulting in decreased renal blood flow, which can result in renal ischemia, tubular dysfunction, and tubular and interstitial fibrosis over time (Schenck et al. 2012). Finally, hypercalcemia can cause mineralization of the renal tubules or interstitium (Kruger et al. 1996; Baloch & LiVolsi 2004). There is a high prevalence of CRD in geriatric animals of all domestic species, though it is only anecdotally reported in pot-bellied pigs. In response to renal injury, the initial adaptive response of the kidney is hypertrophy of the remaining nephrons to maintain glomerular filtration rate. Angiotensin II, local prostaglandins, and nitric oxide mediate preferential vasodilation of the afferent arterioles, promoting glomerular hypertension and hyperfiltration. According to the hyperfiltration theory, this leads to glomerular endothelial damage and increased protein flux, with resulting glomerular sclerosis and nephron loss. As an increasing number of nephrons are lost, total renal function becomes increasingly impaired (Brenner et al. 1996; Polzin 2010). Serum calcium levels in patients with CRD are typically normal or low due to decreased calcitriol synthesis in the kidney, which results in reduced intestinal and renal calcium absorption and reduced negative feedback on the parathyroid. This reduction in negative feedback, combined with parathyroid stimulation by elevated phosphorus levels, triggers parathyroid hyperplasia (Polzin 2010). Subsequent autonomous hypersecretion of PTH is termed renal secondary hyperparathyroidism. Rarely, patients with chronic secondary hyperparathyroidism progress to tertiary hyperparathyroidism, in which nodular hyperplasia leads to PTH hypersecretion that is not suppressed by elevated ionized Ca (Mac Way et al. 2012). Clinically, this is manifested as hypercalcemia and very high serum PTH concentration.
199
It is plausible, then, that the patient described in this report suffered from primary, idiopathic CRD, which resulted in secondary hyperparathyroidism and, ultimately, tertiary hyperparathyroidism. However, examination of serial blood work leading up to her presentation shows that this patient never demonstrated hypocalcemia or hyperphosphatemia, as would be expected had she experienced a period of renal or nutritional secondary hyperparathyroidism. In fact, phosphorus levels remained normal or below normal during that time, while total Ca started within the reference range before trending upward. Furthermore, the patient’s creatinine and BUN remained low or normal until March 2012 and August 2012, respectively, while hypercalcemia and isosthenuria were first documented in May 2010 and October 2011, respectively. This suggests that the patient’s clinical signs were likely the result of PHPT with the later development of CRD. However, the exact relationship between the patient’s CRD and PHPT remains unclear. The clinical, gross, and histological findings in the case reported here are consistent with primary multinodular parathyroid gland hyperplasia, leading to the excessive, unregulated excretion of PTH and resultant hypercalcemia and mild hypophosphatemia. The chronic hypercalcemia may have caused or contributed to the development of CRD by driving chronic hyperfiltration, renal vasoconstriction, and subsequent glomerular sclerosis and nephron loss (Brenner et al. 1996). Alternatively, the patient may have experienced concurrent, independently occurring PHPT and primary CRD. Although CRD is anecdotally described as a disease encountered in geriatric pot-bellied pigs, to the authors’ knowledge, this is the first report of either PHPT or chronic renal failure in a Vietnamese pot-bellied pig.
Acknowledgements The authors would like to thank the pig’s owner for their dedication. The authors would also like to thank the radiologists, clinical pathologists, and staff at the University of Illinois Veterinary Teaching Hospital for their excellent patient care.
Notes 1. 2.
Mazuri Mini Pig Elder. PTH and PTHrP assays performed at the Diagnostic Center for Population and Animal Health at Michigan State University, East Lansing, USA.
References Baloch ZW, LiVolsi VA. 2004. Parathyroid glands. In: Martini L, editor. Encyclopedia of endocrine diseases. New York (NY): Elsevier; p. 505–512. Baylis PH, Milles JJ, Wilkinson R, Heath DA. 1981. Vasopressin function in hypercalcaemia. Clin Endocrinol. 15:343–351. Berger B, Feldman EC. 1987. Primary hyperparathyroidism in dogs: 21 cases (1976–1986). J Am Vet Med Assoc. 191:350–356. Brenner BM, Lawler EV, Mackenzie HS. 1996. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int. 49:1774–1777.
200
S.E. Dumas et al.
DeVries SE, Feldman EC, Nelson RW, Kennedy PC. 1993. Primary parathyroid gland hyperplasia in dogs: six cases (1982–1991). J Am Vet Med Assoc. 202:1132–1136. Feldman EC. 2010. Disorders of the parathyroid glands. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine. 7th ed. St. Louis (MO): Saunders Elsevier; p. 1722–1751. Garofeanu CG, Weir M, Rosas-Arellano MP. 2005. Causes of reversible nephrogenic diabetes indipidus: a systematic review. Am J Kidney Dis. 45:626–637. Ghandur-Mnaymneh L, Kimura N. 1984. The parathyroid adenoma: a histopathologic definition with a study of 172 cases of primary hyperparathyroidism. Am J Pathol. 115:70–83. Krook L. 1957. Primary hyperparathyroidism in the dog. Acta Pathologica et Microbiologica Scandinavica. 41:27–39. Kruger JM, Osborne CA, Nachreiner RF, Refsal KR. 1996. Hypercalcemia and renal failure: etiology, pathophysiology, diagnosis, and treatment. Vet Clin North Am Small Anim Pract. 26:1417–1445. Mac Way F, Lessard M, Lafage-Proust MH. 2012. Pathophysiology of chronic kidney disease-mineral and bone disorder. Joint Bone Spine. 79:544–549. Merck Veterinary Manual. 2013. Hematological reference ranges and serum biochemistry reference ranges [Internet]. [Cited 2013 Mar 8]. Available from: http://www. merckmanuals.com/vet/appendixes/reference_guides/ hematologic_reference_ranges.html
Peterson ME, Randolph JF, Zaki FA, Heath H. 1982. Multiple endocrine neoplasia in a dog. J Am Vet Med Assoc. 180:1476–1478. Polzin DJ. 2010. Chronic kidney disease. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine. 7th ed. St. Louis (MO): Saunders Elsevier; p. 1990–2021. Rainsford KD, Stetsko PI, Sirko SP, Debski S. 2003. Gastrointestinal mucosal injury following repeated daily oral administration of conventional formulation of indomethacin and other non-steroidal anti-inflammatory drugs to pigs: a model for human gastrointestinal disease. J Pharm Pharmacol. 55:661–668. Rijnberk A, Hazewinkel HAW. 1996. Parathyroids. In: Rijnberk A, editor. Clinical endocrinology of dogs and cats. Dordrecht: Kluwer Academic Publishers; p. 167–176. Schenck PA, Chew DJ, Nagode LA, Rosol TJ. 2012. Disorders of calcium: hypercalcemia and hypocalcemia. In: DiBartola SP, editor. Fluid, electrolyte, and acid-base disorders in small animal practice. 4th ed. St. Louis (MO): Saunders; p. 120–194. Stapleton GN, Marks IN, Fourie AJ, McLeod H, Hickman R, Mall A, Terblanche J. 1989. Sucralfate in the prevention of porcine experimental peptic ulceration. Am J Med. 86:21–22. van Vonderen IK, Kooistra HS, Peeters ME, Rijnberk A, van den Ingh TS. 2003. Parathyroid hormone immunohistochemistry in dogs with primary and secondary hyperparathyroidism: the question of adenoma and primary hyperplasia. J Comp Pathol. 129:61–69.
