Anemia, Myopathy, and/or Steatitis in New World Monkeys—Vitamin E and/or Selenium Deficiency?
Abstract
Vitamin E and selenium are micronutrients with a prominent involvement in diseases of animals, including fish, birds, reptiles, and mammals.1,5,6,8-10,12-16,18 In primates, there are reports of spontaneous and experimental hemolytic anemia, myopathy, and/or steatitis associated with vitamin E deficiency and/or positive response to vitamin E/selenium therapy.1,4,5,10-14 The purpose of this communication is to describe the clinicopathologic findings of suspected vitamin E/selenium deficiency in three common marmosets (Callithrix jacchus) and two squirrel monkeys (Saimiri sciureus) that presented either for clinical examination or necropsy.
Case number 1, an underweight (260 g) 2-yr-old male common marmoset, was submitted for necropsy with a prolonged course of non-specific signs. Gross pathology was unremarkable except for muscle atrophy and fecal retention. Pyogranulomatous and fibrosing steatitis of abdominal fat was the most prominent microscopic finding; macrophages surrounding adipocytes had a PAS- and ZN-positive, finely granular cytoplasm, consistent with ceroid. Other lesions were: degenerative myopathy of the diaphragm; myocardial fibrosis; histiocytosis and increased erythrophagocytosis in lymph nodes; hemosiderosis of the reticuloendothelial system and hepatocytes; nephrocalcinosis; and serous atrophy of fat.
Case number 2, a 3-yr-old male common marmoset, presented with anorexia and alopecia of the tail and forelimbs. The diet consisted of a commercial fruit mix, insects and occasionally yogurt, cooked meat, and fish. Calcium and a multivitamin supplement that lacks vitamin E and selenium were used. Alopecia improved in association with protein supplementation over a 2-mo period, with body weight ranging 300–340 g. Six months later, this marmoset presented with a 2-wk history of anorexia, weight loss (268 g) and hindlimb paresis. Alopecia was still present in the left forelimb. CBCs revealed leukopenia with neutrophilia, eosinophilia and lymphopenia, and thrombocytopenia. CPK Value was 465 IU/L. The animal was given ivermectin (Ivomec®, Merck Sharp & Dohme B.V., Haarlem, The Netherlands; 200 µg/kg p.o.) and vitamin E (225 IU/kg) with sodium selenite (1.15 mg/kg) (Toco-Selenio®, Calier, Barcelona, Spain; p.o., once every 3 days for 1 mo). Cessation of paresis and return to normal activity and weight was noted after 1-mo therapy, what was considered significant as therapy did not begin until 2 wk after presentation and clinical signs remained unchanged during that time; however, a temporal coincidence cannot be ruled out. A diagnosis of vitamin E/selenium-responsive myopathy and/or neuropathy was made. Although CPK was not elevated, nutritional myopathy is usually episodic and CPK is short-lived;18 thus myopathy cannot be ruled out on the basis of normal CPK value alone.
Case number 3 was a 3-yr-old female common marmoset with a 2-mo history of weight loss and alopecia. The diet consisted of commercial cereal and fruit mixes with honey, insects, fruits and vegetables, and multivitamin and mineral supplements that lacked vitamin E and selenium. Clinical examination revealed emaciation (220 g), marked alopecia of the tail and head, and enlarged, dark inguinal lymph nodes. A soft mass was palpated just caudoventral to the liver; radiographically, it was moderately and uniformly radiopaque. The animal was given ivermectin as above. CBCs revealed marked anemia, leukopenia with neutrophilia and lymphopenia, and thrombocytopenia. There was mild hypoproteinemia with marked hypoalbuminemia and hyperbetaglobulinemia. Protein supplements and arabic gum were used, and the owner was informed about the possibility of hypoglycemic episodes. Two weeks later the owner reported increasing appetite and body weight (238 g). At that time, CPK, LDH, and AST were markedly elevated, and anemia was characterized as regenerative with <1% of Heinz bodies. A presumptive diagnosis of vitamin E/selenium deficiency was made. The owner used wheat germ oil instead of the recommended vitamin E-selenium product. Three weeks after presentation the marmoset was found comatose; the owner recovered it by heating and giving juice with sugar. The animal died 2 mo after presentation and was not submitted for necropsy.
Case number 4 corresponded to two young-adult squirrel monkeys with a progressively deteriorating body condition. Both animals had been fed dog food and home-made meals for 6 mo and did not have access to sunlight. The female was reluctant to move and manifested pain when handled. The male presented with weight loss (520 g), impaired locomotion, and diffuse moderate alopecia. CBCs revealed moderate anemia, hypoproteinemia, and hypoalbuminemia, and marked hyperbetaglobulinemia. ALP was elevated and calcium low. CPK and AST values were normal. At necropsy, the female was emaciated and had diarrheic feces. The gastrointestinal contents were liquid. Major microscopic findings were fibrosing and degenerative cardiomyopathy with lipofuscinosis and cardiomyocyte atrophy, and necrosis and saponification of pericardial, mediastinal, and perirenal fat. Mild degenerative myopathy was also present. In the kidneys, a granular eosinophilic material was present in numerous convoluted tubules. Other lesions were: diffuse hepatic fatty change; hemosiderosis of the reticuloendothelial system; disseminated intravascular coagulation; and focal suppurative gastritis. A presumptive diagnosis of nutritional osteomalacia and vitamin E/selenium deficiency was made, and treatment with vitamin E (3.75 IU/kg) and vitamin D3 (5,000 IU/kg) (Veterín Vit.® A+D3+E; p.o., once weekly) was initiated in the male. However, it was lost for followups.
Although inconclusive since vitamin E/selenium analyses were not performed, the clinicopathologic findings are suggestive of vitamin E/selenium deficiency. Enhanced peroxidative hemolysis has been induced in vitamin E-deficient common marmosets11 and is one of the features of spontaneous hemolytic anemia of owl monkeys (Aotus trivirgatus), that is associated with vitamin E deficiency and myopathy.13 Similar syndromes have been documented as major mortality factors in colonies of moustached tamarins (Saguinus labiatus)1 and common marmosets4. Excessive Heinz body counts help diagnose hemolytic anemia in these species. Marmoset number 2 had marked regenerative anemia with normal Heinz body counts, associated with elevations of enzymes consistent with muscular damage. Excessive Heinz body counts were a common but not constant finding in a common marmoset colony with a high incidence of hemolytic anemia, myopathy, and undetectable vitamin E levels in some of the affected animals.4
Degenerative myopathy, that was present in the two necropsy cases, may support a diagnosis of vitamin E deficiency since it was a common finding in vitamin E-deficient moustached tamarins, common marmosets, and owl monkeys, and has been experimentally induced in several primate species by feeding vitamin E-deficient diets. Fibrosing and degenerative cardiomyopathy was a prominent finding in the female squirrel monkey and has been reported in vitamin E-deficient gelada baboons (Theropithecus gelada)10 and mountain gorillas12. Experimental selenium deficiency has been induced in squirrel monkeys fed a diet adequate as for its vitamin E contents; alopecia and degenerative myopathy were also observed.14 In rhesus monkeys, experimental selenium deficiency induced cardiomyopathy only in association with dietary protein deficiency.3
Steatitis, a prominent finding in marmoset number 1, has been reported in vitamin E-deficient moustached tamarins1, and in fish-eating crocodilians and birds, mink, and cats suspected or known to be vitamin E-deficient8,15; steatitis has also been experimentally induced in vitamin E-deficient animals such as rats5. Steatitis is a sensitive indicator of vitamin E deficiency in animals fed on diets rich in polyunsaturated fatty acids; adequate vitamin E status depends on the type of dietary fats.5
Fat malabsorption is another possible cause of vitamin E deficiency. Fat malabsorption, with subsequent vitamin E deficiency, altered cholesterol metabolism and red blood cell membrane lipid composition, has been suggested as the underlying problem in owl monkeys with hemolytic anemia and myopathy.13 Fat malabsorption mostly occurs in exocrine pancreatic insufficiency (EPI); dogs with EPI usually have low vitamin E levels.20 In human beings, cystic fibrosis is a cause of EPI; one of its complications is hemolytic anemia in vitamin E-deficient infants.19 The most common cause of EPI is pancreatic acinar atrophy (PAA).20 In primates, PAA and impaired exocrine pancreatic function have been experimentally induced in rhesus monkeys (Macaca mulatta), with concurrent myopathy,4 and patas monkeys (Erythrocebus patas)7 by protein-deficient diets. PAA and fibrosis were prominent in marmosets with wasting marmoset syndrome (WMS), hindlimb paresis and paralysis and degenerative myopathy suspected to be associated with protein deficiency.2 Marmoset number 3 and the male squirrel monkey had hypoproteinemia and/or hypoalbuminemia with no biochemical evidence of renal or hepatic damage, thus suggesting dietary protein deficiency and/or enteric loss. Interestingly, pancreas disease of salmonids, characterized by PAA and fibrosis, is associated with hypoproteinemia, hypoalbuminemia, degenerative myopathy, and vitamin E/selenium deficiency.6 Another possible cause of EPI is chronic pancreatitis20, that has been found in marmosets with the pancreatic worm Trichospirura leptostoma and WMS17.
Pancreatic lesions were not found in the necropsy cases of this report, but protein deficiency and any other cause of EPI should be considered as possible concurrent or even primary factors in the pathogenesis of WMS in callitrichids and any syndrome associated with anemia, myopathy, and/or steatitis and suspected vitamin E/selenium deficiency in primates.
Callitrichids have high protein requirements, so some home-made diets may be protein-deficient for these species. Most marmosets attended at our institution have similar diets and usually present with WMS. Some of these animals seem to respond to protein supplementation.
The possibility of vitamin E/selenium and/or protein deficiency-induced WMS in callitrichids should be carefully investigated through intensive antemortem testing (CBCs with characterization of anemias; total proteins and protein profile; serum chemistries including CPK, LDH, AST, ALT, amylase, lipase, and cholesterol; circulating vitamin E and selenium levels; and, if indicated and possible, exocrine pancreatic function tests and lipoprotein profile), together with nutritional analyses, and postmortem studies (pathology and tissue vitamin E and selenium levels).
Literature Cited
1. Baskin GB, RH Wolf, CL Worth, K Soike, SV Gibson, JG Bieri. 1983. Anemia, steatitis and muscle necrosis in marmosets (Saguinus labiatus). Lab. Anim. Sci. 33: 74–80.
2. Brack M, H Rothe. 1981. Chronic tubulointerstitial nephritis and wasting disease in marmosets (Callithrix jacchus). Vet. Pathol. 18 (Suppl. 6): 45–54.
3. Butler JA, PD Whanger, NM Patton. 1988. Effects of feeding selenium deficient diets to rhesus monkeys (Macaca mulatta). J. Am. Coll. Nutr. 7: 43–56.
4. Chalmers DT, LB Murgatroyd, PF Wadsworth. 1983. A survey of the pathology of marmosets (Callithrix jacchus) derived from a marmoset breeding unit. Lab. Anim. 17: 270–279.
5. Farwer SR, BCJ der Boer, E Haddeman, GAA Kivits, A Wiersma, BHJC Danse. 1994. The vitamin E nutritional status of rats fed on diets high in fish oil, linseed oil or sunflower seed oil. Brit. J. Nutr. 72: 127–145.
6. Ferguson HW, DA Rice, JK Lynas. 1986. Clinical pathology of myodegeneration (pancreas disease) in Atlantic salmon (Salmo salar). Vet. Rec. 119: 297–299.
7. Gry K, RH Wolf, AR Imondi, O Felsenfeld. 1975. Exocrine pancreatic function in protein-deficient patas monkeys studied by means of a test meal and an indirect pancreatic function test. Gastroenterology. 68: 488–494.
8. Larse RE, C Buergelt, PT Cardeilhac, ER Jacobson. 1983. Steatitis and fat necrosis in captive alligators. J. Am. Vet. Med. Assoc. 183: 1202–1204.
9. Liu S, EP Dolensek, CR Adams, JP Tappe. 1983. Myelopathy and vitamin E deficiency in six Mongolian wild horses. J. Am. Vet. Med. Assoc. 183: 1266–1268.
10. Liu S, EP Dolensek, JP Tappe, J Stover, CR Adams. 1984. Cardiomyopathy associated with vitamin E deficiency in seven gelada baboons. J. Am. Vet. Med. Assoc. 185: 1347–1350.
11. McIntosh GH, FH Bulman, JW Looker, GR Russell, M James. 1987. The influence of linoleate and vitamin E from sunflower seed oil on platelet function and prostaglandin production in the common marmoset monkey. J. Nutr. Sci. Vitaminol. (Tokyo) 33: 299–312.
12. McNamara T, EP Dolensek, S Liu, ED Dierenfeld. 1987. Cardiomyopathy associated with vitamin E deficiency in two mountain lowland gorillas. Proc. Int. Conf. Zool. Avian Med. 1: 493.
13. Meydani SN, RJ Nicolosi, PK Sehgal, KC Hayes. 1983. Altered lipoprotein metabolism in spontaneous vitamin E deficiency of owl monkeys. Am. J. Clin. Nutr. 38: 888–894.
14. Muth OH, PH Weswig, PD Whanger, JE Oldfield. 1971. Effect of feeding selenium-deficient ratio to the subhuman primate (Saimiri sciureus). Am. J. Vet. Res. 32: 1603–1605.
15. Nichols DK, VL Campbell, RJ Montali. 1986. Pansteatitis in great blue herons. J. Am. Vet. Med. Assoc. 189: 1110–1112.
16. Orr JP, BR Blakley. 1997. Investigation of the selenium status of aborted calves with cardiac failure and myocardial necrosis. J. Vet. Diagn. Invest. 9: 172–179.
17. Pfister R, K Heider, B Illgen, R Beglinger. 1990. Trichospirura leptostoma: a possible cause of wasting disease in the marmoset. Z. Versuchstierkd. 33: 157–161.
18. Smith GM, JM Fry, JG Allen, ND Costa. 1994. Plasma indicators of muscle damage in a model of nutritional myopathy in weaner sheep. Aust. Vet. J. 71: 12–17.
19. Wilfond BS, PM Farrell, A Laxova, E Mischler. 1994. Severe hemolytic anemia associated with vitamin E deficiency in infants with cystic fibrosis. Implications for neonatal screening. Clin. Pediatr. (Phila) 33: 2–7.
20. Williams DA. 1989. Exocrine pancreatic disease. In: Ettinger SJ, ed. Textbook of Veterinary Internal Medicine. vol. 2, 3rd ed. W.B. Saunders Co., Philadelphia, Pennsylvania, Pp. 1529–1554.