Successful Therapy of Vitamin D-Dependant Rickets in a Kitten

John M. MacKenzie, DVM, DACVIM*, Jason Crawford, DVM, DACVR*, Seth Ghantous, DVM, DACVIM*

Abstract
A 7 mo old, 2.4 kg, intact female kitten was evaluated for an inability to walk after falling out of the owner’s arms. Diagnostic testing abnormalities included hypocalcemia, low ionized calcium, and elevated intact parathyroid hormone concentration. The 25-hydroxyvitamin D level was normal. Radiographic abnormalities included generalized osteopenia, a nondisplaced, folding fracture of the proximal right fibula, and sclerosis with a compression fracture of the proximal right tibia. Based on these findings and response to calcium carbonate and calcitriol therapy, a diagnosis of vitamin D-dependent rickets was made. Reports of similar cases in veterinary medicine are sparse and no other reports to date document radiographic abnormalities with a successful therapeutic outcome. (J Am Anim Hosp Assoc 2011; 47:—–—. DOI 10.5326/JAAHA-MS-5610)

Introduction
A 7 mo old, 2.4 kg, intact female kitten was evaluated for an inability to walk after falling out of the owner’s arms. The kitten and its littermates were rescued soon after birth and were hand-raised by the owners. The kittens were hand-fed kitten replacer formula then weaned to a commercial dry kitten food. The owners reported that the one kitten had an abnormal gait with bilateral forelimb valgus and rear limb “bowing” for the last several months. In addition, the kitten was not as active as the other kittens in the litter. According to the owners, all of the other kittens in the litter were clinically normal and healthy. All kittens had been vaccinated, and no other medical problems were reported.

Case Report
On initial examination, the kitten was responsive, had normal vital signs, a nonpainful, mildly distended abdomen, was tetraparetic with reluctance to walk, and had pain on palpation of the right distal pelvic limb. Initial diagnostic testing included a complete blood count, biochemical profile, feline retrovirus screening, ionized calcium, and radiographs of the whole body. Biochemical abnormalities included low total calcium (4.8 mg/dL; reference range, 7.8–11.3 mg/dL) and low ionized calcium (0.77 mmol/L; reference range, 1.20–1.32 mmol/L). Radiographic abnormalities included a mild, generalized osteopenia that was most notable in the dorsal spinous processes of the vertebra and ribs (Figure 1), osteopenia of the scapulae, which were bilaterally shortened and blunted along the dorsal borders (Figure 2), thinning of the proximal and distal metaphyseal cortices of the long bones, bowing of the radius and ulna in a thoracic limb, and mild bowing of both femurs. The distal radial and ulnar metaphyses were widened in both front limbs; there was a nondisplaced, folding fracture of the proximal right
fibula; and sclerosis with a compression fracture of the proximal right tibia (Figure 3). The physes of the long bones and vertebrae were normal.

Differential diagnoses for the hypocalcemia included primary hypoparathyroidism, nutritional secondary hyperparathyroidism, intestinal malabsorption, acute pancreatitis, vitamin D deficiency (including vitamin D-dependent rickets, type I or II), and toxicoses. Possible explanations for the radiographic abnormalities included osteogenesis imperfecta, osteomalacia, mucopolysaccharidosis, disturbance of normal ossification (rickets), and nutritional secondary hyperparathyroidism.

Further diagnostic testing revealed an elevated intact parathyroid hormone concentration (33.90 pmol/L; reference range, 0.00–4.00 pmol/L) in the face of a low ionized calcium (0.74 mmol/L; reference range, 1.00–1.40 mmol/L), and a normal 25-hydroxyvitamin D level (71 mmol/L; reference range, 65–170 nmol/L). The low ionized calcium and elevated parathyroid hormone concentration were consistent with a secondary hyperparathyroidism typically seen with either renal disease or a nutritional deficiency of vitamin D. There were no other indications of renal insufficiency, and the concentration of 25-hydroxyvitamin D was within the reference range, suggesting adequate intake and absorption of vitamin D. Based on these tests, a presumptive diagnosis of either vitamin D-dependent rickets type I (VDDRI) or vitamin D-resistant rickets type II (VDRRII) was made. Ideally, confirmation of an elevated circulating calcitriol (1,25-dihydroxycholecalciferol) level would have been measured to differentiate between VDDRI and VDRRII; however, such a test was not commercially available. Treatment was initiated with IV lactated Ringer’s solutiona (2.2 mL/kg/hr), a bolus of 10% calcium gluconateb (1 mL/kg IV over 20 min) with monitoring using an electrocardiogram during administration, followed by a continuous rate infusion of 10% calcium gluconate in 0.9% NaClc administered at a rate of 5 mL/hr. Total calcium increased to 6.3 mg/dL following the initial calcium bolus, and both total and ionized calcium returned to normal after administration of the continuous rate infusion after 7 days of therapy. Once the kitten resumed eating, oral therapy included calcium carbonated (75 mg/kg q 8 hr) and calcitriole (40 ng [16.7 ng/kg] q 12 hr). A relatively high dose of calcitriol was initially prescribed to hypothetically supersaturate the vitamin D receptors in the event that the kitten had VDRRII. The right hind limb was casted upon identification rediographically of the fracture and IV buprenorphinef was administered q 4 hr for pain.

The kitten was re-evaluated 4 days following discharge fromthe hospital. Total calcium was at the low end of normal (7.8 mg/dL) and ionized calcium remained low (0.97 mmol/L; reference range, 1.20–1.32 mmol/L). The calcitriol dose was increased to 50 ng (20.8 ng/kg) per os (PO) q 12 hr. Ten days following hospital discharge, the kitten had a normal ionized calcium (1.20 mmol/L; reference range, 1.00–1.40 mmol/L), elevated alkaline phosphatase (134 U/L; reference range, 14–111 U/L), and radiographic evidence of healing of the right tibia and fibula fractures. Three weeks following previous appointment, the right tibia and fibula fractures were healed, and total and ionized calcium values remained within the normal ranges (10.0 mg/dL and 1.28 mmol/L; reference range, 1.00–1.40 mmol/L, respectively). Four months after the initial diagnosis, the kitten weighed 2.8 kg, had normal total calcium (9.8 mg/dL), normal ionized calcium (1.22 mmol/L; reference range, 1.20–1.32 mmol/L), and a mildly elevated alkaline phosphatase (136 U/L). Based on total and ionized calcium values, calcitriol tapering was initiated, decreasing the dose by 25–50% per day q 3–4 mo. One year after the initial diagnosis, the kitten was thriving, had a normal appetite and energy level, weighed 3.5 kg, and had no ill-effects from the right tibia and fibula fractures. The axial skeleton was radiographically normal with no evidence of osteopenia including the dorsal spinous processes (Figure 4) and scapula. The total calcium (9.9 mg/dL) and ionized calcium (1.25 mmol/L; reference range, 1.13–1.38 mmol/L) values remained in the normal range. Parathyroid hormone levels were also normal (3.00 pmol/L). The calcium carbonate was discontinued and the calcitriol dose was decreased from the initial dose of 50 ng PO q 12 hr to 20 ng PO q 24 hr.

Discussion

Classic rickets, a disturbance of normal ossification, often includes widened growth plates, splaying of metaphyses, and poor skeletal mineralization.1,2 In people, four forms of rickets have been identified. These include: nutritional rickets from dietary deficiency of vitamin D or phosphorous; hereditary X-linked hypophosphatemia rickets; VDDRI (a defect in calcitriol production); and vitamin Ddependent rickets type II (an impaired responsiveness of target organs to calcitriol due to vitamin D receptor defects).3 Vitamin D-dependent rickets type II is also termed hereditary vitamin Dresistant rickets (HVDRR). VDRRII is caused by an inherited, autosomal recessive impaired response of target organs to calcitriol due to a functional mutation in the gene encoding the vitamin D receptor.1,3,4 Ideally, confirmation of elevated circulating calcitriol (1,25-dihydroxycholecalciferol) levels are obtained to differentiate between VDDRI and VDRRII; however, this test is not commercially available. In VDDRI patients, circulating calcitriol levels are low, whereas in VDRRII patients, circulating calcitriol levels are high.

In humans, VDRRII is caused by an inherited, autosomal recessive impaired response of target organs to calcitriol due to the functional mutation in the gene encoding the vitamin D receptor.4 In human patients, response to therapy in patients with VDRRII is considered good; however, very few reports exist, and even fewer describe cases with successful long-term therapy.1 A recent report of an intact female Pomeranian suspected of having VDRRII, documented a vitamin D receptor gene mutation that resulted in HVDRR.5 The authors of that study attributed the molecular basis for HVDRR to a one base pair deletion in exon 4 that caused a frameshift and introduced a premature stop in exon 5. That dog was treated with high doses of calcium carbonate and calcitriol unsuccessfully.

Reports of similar feline cases in veterinary medicine are sparse. Previous reports have included two 4 mo old kittens, one with and one without radiographic skeletal abnormalities. The patient without radiographic skeletal abnormalities had a normal serum calcium level with elevated parathyroid hormone and calcitriol levels, but only survived to 13 mo of age.1 A report of a 4 mo old kitten with hypocalcemia and radiographic abnormalities similar to the patient described in this study did not have resolution of the hypocalcemia or radiographic abnormalities, despite aggressive calcium carbonate and calcitriol therapy.6 In one report, two kittens with unusual metaphyseal disturbances were initially suspected of having VDRR, but were instead diagnosed with metaphyseal chondrodysplasia.7 A previous report discussed a diagnosis of VDDRII in a 5 mo old cat with hypocalcemia, skeletal demineralization, elevated parathyroid hormone levels, and normal 25 hydroxycholecalciferol levels.8 Additionally, 1,25-dihydroxycholecalciferol levels, which are no longer commercially available, were low. That kitten was treated successfully with a lower dose of calcitriol (25 ng/kg/day) compared with the dose used unsuccessfully (43.8 ng/kg/day) in the 4 mo old kitten with VDRRII described above.6 Therefore, based on the authors’ lack of confirmation of either VDDRI or VDRRII in the present case, an escalating calcitriol dose eventually reaching a total dose of 100 ng/day was prescribed to achieve calcium homeostasis within 10 days. This did not allow the authors to rule out VDDRI; however, the dose of calcitriol required was higher than the calcitriol dose needed to resolve this disease process by Geisen et al (2009).8 Normal functioning vitamin D receptors in the kidney are required for feedback suppression of calcitriol synthesis; therefore, in cases of VDRRII, the functional mutation in the gene encoding the vitamin D receptor results in a high plasma calcitriol level.4 Calcitriol increases the absorption of dietary calcium from the intestinal tract, is required for bone mineralization during skeletal growth, and potentially stimulates retention of calcium and phosphorous in the kidney through increased proximal tubular resorption. Calcitriol is formed from the metabolism of cholecalciferol that is either ingested through the diet or synthesized in the epidermis from 7-dehydrocholesterol.3 Because the skin of dogs and cats contains only small amounts of 7-dehydrocholesterol, there is an inadequate amount of production of cholecalciferol, thus requiring them to depend on their diet as a source of calcitriol precursors.3 This leads to the findings of hypocalcemia and hyperparathyroidism and the activation of the enzyme 1-ahydroxylase in the kidney, which increases calcitriol production from vitamin D.9

Conclusion
Documentation of serum calcitriol for this case was not performed due to the absence of a commercially available test. The findings of hypocalcemia, poor skeletal mineralization, and hyperparathyroidism, coupled with a clinical response to presumptive supersaturating of the calcitriol receptors via high calcitriol dosing, could support a diagnosis of VDRRII. Based on the successful therapy following this presumptive supersaturation of the vitamin D receptors and theoretically compensating for impaired binding of calcitriol to vitamin D receptors, this case demonstrates that the prognosis in cats with presumptive VDRRII can be good and that implementation of a similar therapeutic approach is warranted. With larger doses of calcitriol, high blood levels can be achieved, allowing receptor binding and activation of the receptor without any detrimental side effects. Once stable ionized serum calcium levels have been achieved, the high initial dose of calcitriol should be continued throughout the cat’s juvenile life stage. As cats reach adulthood, they still require elevated calcitriol supplementation, but the dose may be reduced to approximately one-quarter of initial dosing, as adults no longer require the same degree of bone growth and remodeling as kittens do.

FOOTNOTES
a. Lactated ringers; Hospira, Inc., Lake Forest, IL
b. Calcium gluconate; AAP Pharmaceuticals LLC, Schaumburg, IL
c. 0.9% NaCl; Hospira, Inc., Lake Forest, IL
d. Calcium carbonate; GlaxoSmithKline, St. Louis, MO
e. Calcitriol; 100ng/ml compounded Braun Pharmacy, Chicago, IL
f. Buprenorphine; Benckiser Pharmacy, Inc., Richmond, VA

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