J. small Anim. Pract. (1970) 11, 553-561. Exostoses in hypervitaminotic A cats with optimal calcium-phosphorus in takes LEIGH CLARK, A. A. SEAWRIGHT AND JANA HRDLICKA Department of Preventive Medicine, Veterinary School, University of Queensland, Australia ABSTRACT Exostoses typical of those previously described in chronic hypervita- minosis A of the cat were produced in six cats fed liver selected for high vitamin A content, and in six cats fed mince low in vitamin A and supplemented with the vitamin by capsule. In contrast to the previous work, the mineral content of each diet was adjusted to be more than adequate in calcium and phosphorus and optimal in calcium/phosphorus ratio. It was concluded that the levels and relative proportions of calcium and phosphorus in the diet have little or no influence of the development of exostoses in chronic hypervitaminosis A in the cat, and that the American disease ‘osteodystrophy in mature cats’ probably has a different aetiology. INTRODUCTION Chronic hypervitaminosis A in adult cats is characterized by multiple exostoses, and has been produced in Australia both in cats fed whole liver diets with milk and in cats fed meat and milk and dosed orally with vitamin A for several months (Seawright et al., 1965, 1967). The exostoses are most noticeable on the cervical and thoracic vertebrae, where they may become confluent, and on the fore- limbs. The abnormal bone deposition originates around articular surfaces in regions of ligament and tendon attachment, and trauma has been suggested as a factor determining these predeliction sites (Seawright et al., 1967). Recently ‘eight additional cases of the disease’ were described in America (Riser et al., 1968) but only one case resembled hypervitaminosis A as it is recognized in Australia. In the American disease there was a similar subperiosteal bone proli- feration, but in six of the eight cats the appendicular skeleton was predominantly affected, and whole diaphyses were involved rather than the lesions being restricted to periarticular areas. The diets of these cats were unusually high in 553
Transcript
J . small Anim. Pract. (1970) 11, 553-561.
Exostoses in hypervitaminotic A cats with optimal
calcium-phosphorus in takes
L E I G H C L A R K , A. A. S E A W R I G H T A N D J A N A H R D L I C K A
Department of Preventive Medicine, Veterinary School, University of Queensland, Australia
A B S T R A C T
Exostoses typical of those previously described in chronic hypervita- minosis A of the cat were produced in six cats fed liver selected for high vitamin A content, and in six cats fed mince low in vitamin A and supplemented with the vitamin by capsule. In contrast to the previous work, the mineral content of each diet was adjusted to be more than adequate in calcium and phosphorus and optimal in calcium/phosphorus ratio. I t was concluded that the levels and relative proportions of calcium and phosphorus in the diet have little or no influence of the development of exostoses in chronic hypervitaminosis A in the cat, and that the American disease ‘osteodystrophy in mature cats’ probably has a different aetiology.
I N T R O D U C T I O N
Chronic hypervitaminosis A in adult cats is characterized by multiple exostoses, and has been produced in Australia both in cats fed whole liver diets with milk and in cats fed meat and milk and dosed orally with vitamin A for several months (Seawright et al., 1965, 1967). The exostoses are most noticeable on the cervical and thoracic vertebrae, where they may become confluent, and on the fore- limbs. The abnormal bone deposition originates around articular surfaces in regions of ligament and tendon attachment, and trauma has been suggested as a factor determining these predeliction sites (Seawright et al., 1967). Recently ‘eight additional cases of the disease’ were described in America (Riser et al., 1968) but only one case resembled hypervitaminosis A as it is recognized in Australia. I n the American disease there was a similar subperiosteal bone proli- feration, but in six of the eight cats the appendicular skeleton was predominantly affected, and whole diaphyses were involved rather than the lesions being restricted to periarticular areas. The diets of these cats were unusually high in
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liver and the authors presumed that vitamin A excess was an important factor in the disease, but that the r61e of low calcium and high phosphorus was probably just as important in its pathogenesis. The following experiment was therefore designed to determine the nature of bone lesions produced in hypervitaminosis A when diets are high in calcium and phosphorus and have an optimal calcium/ phosphorus ratio.
M A T E R I A L S A N D M E T H O D S
Two groups of six healthy half-grown cats were used. Group I was fed entirely on sheep livers selected by analysis (Moore, 1957) for high vitamin A content. The cats in Group I1 were fed abattoir pets mince* and were dosed daily with vitamin At by capsule at the rate of 8-50 pg/g-body-weight. Calcium and phos- phorus analyses (A.O.A.C., 1960) were done on several samples of minced sheep liver and abattoir pets mince and these minerals were added in amounts necessary to fulfill the daily requirements for growing cats (Scott, 1965). The liver diet required additional calcium only, and this was supplied in the form of calcium carbonate. The pets mince was found to be deficient in both calcium and phos- phorus, and was balanced with calcium hydrogen orthophosphate and calcium carbonate. Samples were analysed at regular intervals throughout the experiment to ensure that the mineral levels remained fairly constant. The results of these analyses are presented in Table 1. The cats were fed ad lib and daily food intake was measured on a group basis. Once a week the animals were weighed, and radiographs were taken periodically to follow the development of bone lesions.
The animals were destroyed by an injection of barbiturate solution, some during the course of the experiment, but most at the end. At necropsy the liver and kidneys from each cat were weighed and samples taken for vitamin A analysis (Moore, 1957). The skeletons from some cats were entirely macerated, and from others bones were selected for histological examination. These were fixed in neutral 10% formalin, decalcified by the formic acid-sodium citrate method (US . Armed Forces Institute of Pathology, 1949) and paraffin sections were stained with haematoxylin and eosin.
R E S U L T S
Clinical observations The length of treatment and the initial and final weights of the experimental
animals are shown in Table 2. The average daily food intake was 119 g for Group I (liver) and 114 g for Group I1 (mince and vitamin A). All animals gained weight during the experiment but did not retain their initial good condi- tion and sleek coats. A difference in the behaviour of the animals was noticeable
* Produced by the Brisbane Metropolitan Public Abattoir Board. t E. R. Squibb Vitamin A W/M Oral.
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TABLE 1. Mineral and vitamin A status of cat diets
Diet Ca P Ca : P Vitamin A (mgl100 9) (mgl100 g) ratio (mg/100 g)
* Approximate daily requirements for growing cats (Scott, 1965).
after 3-4 months : they became depressed, apprehensive and reluctant to move ; most were hypersensitive to neck palpation and exhibited hesitant limping gaits which became more marked with time. Radiographic evidence of new bone formation was first detected in cat 2 from Group I1 in the tenth week of the experiment. This took the form of a rounded mineralized outgrowth on the lateral surface of the third cervical vertebra, and bony bridges linking several sternebrae dorsally. By the twentieth week exostoses were visible on radiographs of most of the animals remaining in each group.
TABLE 2. Initial and final weights of each experimental hypervitaminotic A cat, with time of necropsy
Initial Final Week Cat Sex weight weight of
(g) (9) necropsy
Group I (liver)
1 M 2 F 3 M 4 M 5 F 6 M
Group I1 (mince and vitamin A)
1 M 2 M 3 F 4 F 5 F 6 F
1050 1450 1000 1050 1550 1600
1400 1300 1500 1850 1400 1450
2100 26 2200 28 2580 30 2075 30 1950 30 2400 30
2840 13 2050 12 2 180 30 2545 30 2300 30 2300 13
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Vitamin A analyses The average vitamin A content of sheep livers fed in the experiment was
52.6 mg/lOO g. By contrast, the average vitamin A content of the mince diet fed to Group I1 was only 0.05 mg/100 g.
The approximate intake of vitamin A by each cat and the concentration and total vitamin A in liver and kidney at necropsy are shown in Table 3. The vitamin
TABLE 3. Approximate vitamin A intake in each cat and liver and kidney concentrations at necropsy
Liver vitamin A Kidney vitamin A Vitamin A intake concentration concentration
A intake of Group I(1iver fed) cats was considerably higher than that of Group 11, which had vitamin A administered by capsule. The high vitamin A intake of both groups caused appreciable storage in the livers and kidneys of all cats, but there was considerable individual variation in storage.
Pathology Multiple exostoses, occurring in regions of tendon, ligament or joint capsule
attachment, were the predominant bone lesions. As the experiment had a course of only 30 weeks, these lesions were small and seldom confluent.
Observations on the distribution of skeletal exostoses are set out in Table 4. Both sides of the skeleton were affected similarly in each cat. The most extensive
E X O S T O S E S I N H Y P E R V I T A M I N O T I C A C A T S 557
lesions involved the cervical vertebrae, and often the exostoses measured several millimetres in diameter. O n the atlas, roughened bony outgrowths were most common centrally on the cranial margin of the dorsal arch (Fig. l a ) , and on the cranial and caudal margins of the wings. The axis was the only bone which was affected in all cats, and in one cat was the only bone in which a lesion was demonstrated. The cranial extremity of the spinous process was invariably roughened and thickened due to osteophyte formation, and often there were similar formations around the caudal articular surfaces. I n two cats these had joined with outgrowths from the cranial articular processes of the third cervical vertebra causing ankylosis of the two bones (Fig. l b ) . Occasionally small out-
TABLE 4. Distribution of exostoses in the twelve experimental animals
Cat Atlas Axis C3 Other Ster- Ribs Sca- Hum- Ra- Ulna Femur verte- num pula erus dius brae
growths were present projecting from the caudal margins of vertebral bodies on the ventral aspect. There was a progressive reduction in cervical lesions passing caudally, and lesions were rarely found on thoracic and lumbar vertebrae.
Sternebrae were frequently affected, particularly in the midsternal region. Roughened proliferations tended to join successive bones dorsally across the inter- vening cartilages (Fig. lc). Less commonly similar projections extended from the extremities of these bones on the ventral aspect. In four cats exostoses were present on some ribs. These mainly involved the head and tubercle, but in some animals bony cuffs extended from several costochondral junctions to partially cover the adjoining rib cartilage (Fig. Id).
EXOSTOSES I N H Y P E R V I T A M I N O T I C A C A T S 559
In the forelimbs macroscopic lesions occurred on the scapula, distal humerus and proximal radius and ulna. Irregular osteophytes sometimes extended from the periarticular region on the caudal border of the scapula (Fig. le) and occasionally the coracoid remnant and metacromion were enlarged and rough- ened. On the humerus the most extensive lesions were on the medial and lateral epicondyles and sometimes the new bone formation had extended dorsally along the lateral condyloid crest (Fig. 1 f ) . Proximally, small osteophytes were sometimes seen in the metaphyseal region, and occasionally the deltoid tuberosity was more prominent than normal and roughened. On the radius, exostosis formation was sometimes evident on the proximo-medial aspect, at the insertion of the brachialis muscle. By contrast, involvement of the proximal ulna was more diffuse and extensive (Fig. Ig). The radius and ulna seldom exhibited lesions distally.
Exostoses were not common on the hindlimbs. When the proximal femur was involved these lesions were seen on both the greater and lesser trochanters (Fig. lh) . Distally, osteophytes were occasionally present on the epicondyles, in some bones with encroachment on the adjacent medial and lateral condylar surfaces.
The histopathology of exostoses was essentially similar to that described by Seawright & English (1964) and Seawright et al. (1967). That is, there was marked localized periosteal proliferation with the formation of irregular masses of woven bone. This was accompanied by increased osteoclastic resorption of the original compacta, and in the apophyseal joints of cervical vertebrae and sternum, by marked cartilaginous hyperplasia. Bone marrow in adjacent areas was com- paratively acellular and fibrous.
In addition to exostoses in areas described above, the skeletons of the experi- mental animals showed further abnormalities. Although strong and well mineral- ized, the diaphyses of the large longbones of the limbs were narrower than normal and displayed marked metaphyseal flaring (Figs. If and h). I n some cats, too, the epiphyseal plates of the distal femur and proximal tibia, which would not be expected to close normally until the eighteenth month (Barone, 1966) showed localized areas of matrix degeneration, and sometimes discontinuity. These
FIG. 1, Selected macerated bones showing characteristic exostoses (arrows). The long- bones also show abnormally narrow shaft diameters and metaphyseal flaring. Natural size. (a) Atlas with exostosis on cranial margin of dorsal arch. (b) Axis with exostosis on cranial extremity of spinous process. The articular processes
of the axis and third cervical vertebra are ankylosed. (c) Sternum showing bony bridges linking successive sternebrae dorsally. (d) Ribs showing typical exostoses. (e) Scapula with developing osteophytes in the periarticular region and on the
metacromion. (f) Humerus with exostoses on medial and lateral epicondyles. ( g ) Proximal ulna showing diffuse exostosis formation. (h) Femur with exostoses on the lesser trochanter and lateral epicondyle.
560 L E I G H C L A R K , A . A . S E A W R I G H T A N D J A N A H R D L I C K A
changes are consistent with those already described by Clark et al. (1970) and Clark (1970) for the effect of hypervitaminosis A on longbone growth in kittens.
D I S C U S S I O N
I n previous work on deforming cervical spondylosis or chronic hypervitaminosis A in the cat (Seawright et al., 1967) the dietary levels of calcium and phosphorus were not stated, but were probably suboptimal due to lack of supplementation. However, both the appearance and distribution of exostoses in the present experi- ment, in which diets were optimal in these minerals, are consistent with the above experimental disease, and with the naturally occurring disease (Seawright & English, 1964). I t would appear that the levels and the relative proportions of calcium and phosphorus in the diet have little or no influence on the development of exostoses in chronic hypervitaminosis A in the cat. As yet there is no evidence that chronic hypervitaminosis A is a causative factor in the cat disease described in America as ‘osteodystrophy in mature cats’ (Riser et al., 1968) although this was considered to be likely due to the liver feeding of these animals. Vitamin A assays were presented for only one of the eight cases described, and the liver level was as low as 5850 pg/g. Liver vitamin A concentrations of this magnitude are common in cats in Australia (Seawright et al., 1968) and experimental evidence suggests that exostoses due to excess of the vitamin would be most unlikely to be present in such an animal (Seawright et al., 1967). Nevertheless lower liver reserves of the vitamin such as this may be present in animals whose skeletons already have extensive exostoses due to hypervitaminosis A, if vitamin A intake has been negligible for about 3 years after the development of these lesions; moreover, cessation of high vitamin A intake is followed by arrestment of the progress of bone lesions (Seawright et al., 1970). I t is suggested then that causative factors other than hypervitaminosis A and possibly even mineral deficiency and imbalance should be sought in the rare osteodystrophy of mature cats charac- terized by extensive diaphyseal subperiosteal new bone formation as described by Riser et al. ( 1968).
R E F E R E N C E S
ASSOCIATION OF OFFICIAL AGRICULTURE CHEMISTS (1960) in Methods of Anabsis. A.O.A.C.,
BARONE, R. ( 1966) In Anatomie Comparie des Mammqeris Domestiques. Laboratoire d’Anatomie
CLARK, L. (1970) J . comb. Path. Ther. 780. (In press.) CLARK, L., SEAWRIGHT, A.A. & GARTNER, R.J. W. (1970) 3. comb. Path. Ther. 80, 1 13. MOORE, T. (1957) In Vitamin A . Elsevier, New York. RISER, W.H., BRODEY, R.S. & SHIRER, J.F. (1968) 3. Am. vet. Radiol. SOL. 9, 37. SCOTT, P.P. (1965) In Canine and Feline Nutritional Requirements. Pergamon Press, Oxford. SEAWRIGHT, A.A. & ENGLISH, P.B. (1964) 3. Path. Bact. 88, 503. SEAWRIGHT, A.A., ENGLISH, P.B. & GARTNER, R.J.W. (1965) Nature, Lond. 206, 117.
Washington.
Ecole Nationale Veterinaire, Lyon.
E X O S T O S E S I N H Y P E R V I T A M I N O T I C A C A T S 56 1
SEAwRIGIiT, A.A., ENGLISH, P.B. & GARTNER, R.J.W. (1967) 3. corn$. Path. Ther. 77, 29. SEAWRIGHT, A.A., ENGLISH, P.B. & GARTNER, R.J.W. (1970) Adv. vet. Sci. 14. (In press.) SEAWRIGHT, A.A., STEELE, D.P. & CLARK, L. (1968) Aust. vet. 3. 44, 203. U.S. ARMED FORCES INSTITUTE OF PATHOLOGY (1949) In Manual of Histologic and Special Staining
Technics. McGraw-Hill, New York, Toronto and London.
Resume. On a provoqut des exostoses dtcrites comme manifestation typique de l’hypervita- minose A du chat en administrant B 6 animaux du foie stlectionnk pour sa forte teneur en vitamine A et a six autres chats du hachis de foie pauvre en cette vitamine, mais suppltmentk par des capsules de vitamines. Contrairement A ce qui a e t t fait dans des etudes antkrieures, les concentrations en xnintraux on et t ajusttes de facon a Etre plus qu’adtquates en ce qui concerne le calcium et le phosphore et le rapport optimal calcium : phosphore. On conclut que les teneurs en calcium et en phosphore ainsi que le rapport entre ces deux tl tments dans le rtgime n’ont que peu ou pas du tout d’influence sur le dkveloppement des exostoses au cows de l’hypervita- minose A chronique du chat et que le syndrome dtcrit par les AmCricains sous le nom de ‘osttodystrophie du chat adulte’ reli-ve sans doute d’une ttiologie difftrente.
Zusammenfassung. Exostosen typisch in der Art, wie sie friiher bei chronischer A-Hyper- vitaminose der Katze besprochen wurden, liessen sich bei sechs Katzen hervorrufen, die mit Leber gefiittert wurden, welche nach ihrem hohen Vitamin-A-Gehalt ausgewahlt worden war, und bei sechs Katzen, die Hackfleisch mit geringem Vitamin-A-Gehalt als Futter erhielten, das durch das Vitamin in Kapseln erganzt wurde. Im Gegensatz z u der friiheren Untersuchung wurde der Mineralgehalt beider Futterarten auf mehr als ausreichend im Calcium- und Phos- phorgehalt und auf optimal hinsichtlich des Calcium/Phosphor-Verhaltnisses eingestellt. Es wurde daraus der Schluss gezogen, dass die Konzentrationen und das Mengenverhaltnis von Calcium und Phosphor im Futter wenig oder keinen Einfluss auf die Entwicklung von Exostosen bei chronischer A-Hypervitaminose bei der Katze hatten und dass die amerikanische Krankheit ‘Osteodystrophie bei erwachsenen Katzen’ wahrscheinlich eine andere Atiologie besitzt.
