ANIMAL MODEL OF HUMAN DISEASE
a1-Antitr-psin Deficiency Animal Model: Round Heart Disease of Turkevs
Contributed by: F. Neumann, Dr Med Vet, PhD, Ruth Meirom, MSc, D. Rattner, MSc, Z. Trainin, Dr Med Vet, U. Klopfer, Dr Med Vet, T. A. Nobel, Dr Med Vet, DTVM, Kimron Veterinary Institute, Bet Dagan, PO Box 12, Israel.
Clnical Features
Turkeys affected with round heart disease (RHD) display respiratory distress and growth retardation. The cardiac activity as investigated bNcatheterization showvs similar features to that observed in congestive cardiopathv in man.' The EKG showvs a right ventricular dilatation.2 and this technique has been suggested as a useful method to screen affected flocks.3 Death occurs mostly in poults aged 2 to 10 weeks. The mortality rate in affected flocks may be 15 to 20%c . The morbidity rate is unknown.
Pathogc Fidings The heart and liver are always affected. The heart is enlarged, due to dilatation of the right or both ventricles, and the wvall of the dilated ventricles is thinner than normal (Figure 1). The mvocardium is flabby. In older birds the endocardium is thickened and opaque. The subepicardial coronary arteries are congested (Figure 2). The liver is enlarged. wvith rounded borders. The parenchvma is hardened and grayish-bro-n. Ascites is a common finding. Interstitial mvocarditis with mononuclear cell infiltration, muscle fiber degeneration s and, in older birds, an endocardial fibroelastosis are reported.5'6 Therefore, Noren et al.7 suggest the RHD of turkeys as a suitable animal model for study of interstitial myocarditis with fibroelastosis in man, as described by Hutchins and Vie.8 Publication sponsored bx- the Registry of Comparativ e Pathology of the Armed Forces Institute of Pathology and supported by Public Health Service Grant RR 00:301 from the Disision of Research Resources. LUS Department of Health. Education and VN elfare. under the auspices of U~nisversities Associated for Research and Education in Pathology. Inc
427
428
NEUMANN ET AL
American Journal of Pathology
--ft;..OOM..,
Figure 1 (left)-Turkey heart showing dilatation of the right ventricle. Figure 2 (rMht)Enlarged heart and
congested subepicar-
dial coronary arteries are seen in this affected turkey heart. -
-7-
Fatty degeneration of liver cells, bile duct proliferation, and nodular mononuclear cell infiltration are generally observed. The liver in older birds display a hvperplastic cirrhosis. The most distinctive lesion is the presence of anhistic intracytoplasmic globules,9 ranging from 2 to 14 g in diameter. The globules appear pink by hematoxylin and eosin staining and give a positive periodic acid-Schiff reaction that is not altered by diastase treatment (Figure 3). By phosphotungstic acid-hematoxylin staining, the globules display a bluish-black color, and the larger globules are surrounded by a clear halo. The globules contain a-globulins as demonstrated by immunofluorescent technique (Figure 4).10 Immunoelectrophoretic analyses of serum sho-w a characteristic aglobulin deficiency in 87%t of affected turkeys (Figure 5)."
q d
Figure 3 (left)-Periodic acid-Schiff-positive intracytoplasmic granules in liver (x 900). Figure 4 (riht)-intracytoplasmic globules which contain a-globulins, as visualized by immunofluorescence technique in liver (x 630).
Vol. 84, No. 2 August 1976
a,-ANTITRYPSIN DEFICIENCY
429
-WW-pal"W.
Fge 5-Disc electrophoresis pattern of turkey sera from normal bird (1) and from turkey with round heart disease, lacking a-globulins (2).
I
2
The trypsin inhibition capacity (TIC) in affected turkeys with RHD is significantly lower than in normal birds. The TIC expressed in milligrams of trypsin inhibited by 1 ml serum in affected turkeys is as follows: 0.655 ± 0.0712 in poults which died with RHD and 0.698 ± 0.0806 in living poults affected with RHD. In the control groups TIC values are: 1.229 ± 0.0487 (t = 6.821, P < 0.001) in the first trial and 1.086 ± 0.126 (t = 2.713, 0.01 < P < 0.025) for the second trial. Turkevs used in each trial were from the same flock and of the same age.12 Comparison Wh a,-Antiftypsin Deficieny
a,-Antitrypsin (AlA) in man is reviewed in all its aspects by Lieberman,13 Kueppers," and Feldmann et al.15 The common features between RHD of turkeys and AlA deficiency in man are the liver lesions and the changes in the blood. In AlA deficiency, identical intracytoplasmic globules are present in liver cells as in RHD of turkeys. In both instances the serum showvs a low antiproteolytic activity. The other cardinal lesions in the two conditions are different, i.e., panemphvsema of the lung in man and heart dilatation in turkeys. In AlA the pathogenesis of the lung emphysema is explained bv the decrease of AlA activity and a subsequent increase in proteolvtic activitv that destrovs the alveolar membrane.13 The pathogenesis of the ventricular dila-
430
NEUMANN ET AL
American Joumal
of Pathology
tation in RHD has not been elucidated, but the same increased proteolytic activity may be involved. a1-Antitrypsin deficiency is a genetically controlled condition, and the genetic aspects of RHD need further investigations. Avaabity
Since Magwood and Bray " reported the first case of RHD in Broad Breasted White turkeys in Canada, the condition has been found in the USA in the above strain 1,S,5,6 and in Nicholas strain.6 We have found the condition in the Nicholas strain, in miniturkeys imported from Holland, and in the BUT strain. Refees 1. Einzig S, Jankus EF, Moller JH: Round heart disease in turkeys: A hemodynamic study. Am j Vet Res 33:557-61, 1972 2. Hunsaker WG, Robertson A, Magwood SE: The effect of round heart disease on the electrocardiogram and heart weight of turkey poults. Poultry Sci 50:1712-1720, 1971 3. Hunsaker WG: Round heart disease in four commercial strains of turkevs. Poultrv Sci 1720-1724, 1971 4. Jankus EF, Good AL: Round heart disease in turkeys. Minn V'et 10:1 1-12, 1970 3. Noren GR, Staley NA, Jankus EF, Stevenson JE: Myocarditis in round heart disease of turkeys: A light and electron microscopic study. Virchows Arch Pathol Anat
352:285-295, 1971 6. Sautter JH, Newman JA, Kleven SH, Larsen CT: Pathogenesis of the round heart svndrome in turkeys. Avian Dis 12:614-628, 1968 Noren GR, Staley NA, Kaplan EL, Jankus EF: An animal model of human disease: Cardiomvopathy. Comp Pathol Bull 6:3-4, 1974 8. Hutchins GM, Vie SA: The progression of interstitial myocarditis to idiopathic endocardial fibroelastosis. Am J Pathol 66:483-496, 1972 9. Neumann F, Klopfer U, Nobel TA, Dison MS, Bendheim U: Peculiar liver changes in round heart disease in turkeys. Vet Rec 98:599-601, 1973 10. Meirom R, Trainin Z, Neumann F, KJopfer U, Dison MS, Rattner D: Alphaglobulin intracytoplasmic hepatocyte globules in round heart disease in turkeys, visualized by inmunofluorescent technique. Poultry Sci 54:1218-1220, 1975 11. Meirom R, Trainin Z, Barnea A, Neumann F, Klopfer U, Nobel TA, Dison NIS, Plesser 0: Hypoproteinemia and alpha globulin deficiency in round heart disease of turkeys. Vet Rec 94:262-264, 1974 12. Rattner D. Deficiency of trypsin-inhibiting capacity in serum of turkeys with round heart disease. J Comp Pathol 86:131-133, 1976 13. Lieberman J: Alpha,-antitr psin deficiency. Med Clin N Am 37:691-706, 1973 14. Kueppers F: Human alpha1-antitrypsin. Environ Res 6:403-423, 1973 15. Feldmann G, Bignon J, Chahinian P: The liver in alpha,-antitrv`psin deficiency. Digestion 10:162-174, 1974 16. Magwood SE, Bray DF: Disease condition of turkeys poults characterized by enlarged hearts. Can J Comp NMed V7et Sci 26:268-272, 1962
a1-Antitr-psin Deficiency Animal Model: Round Heart Disease of Turkevs
Contributed by: F. Neumann, Dr Med Vet, PhD, Ruth Meirom, MSc, D. Rattner, MSc, Z. Trainin, Dr Med Vet, U. Klopfer, Dr Med Vet, T. A. Nobel, Dr Med Vet, DTVM, Kimron Veterinary Institute, Bet Dagan, PO Box 12, Israel.
Clnical Features
Turkeys affected with round heart disease (RHD) display respiratory distress and growth retardation. The cardiac activity as investigated bNcatheterization showvs similar features to that observed in congestive cardiopathv in man.' The EKG showvs a right ventricular dilatation.2 and this technique has been suggested as a useful method to screen affected flocks.3 Death occurs mostly in poults aged 2 to 10 weeks. The mortality rate in affected flocks may be 15 to 20%c . The morbidity rate is unknown.
Pathogc Fidings The heart and liver are always affected. The heart is enlarged, due to dilatation of the right or both ventricles, and the wvall of the dilated ventricles is thinner than normal (Figure 1). The mvocardium is flabby. In older birds the endocardium is thickened and opaque. The subepicardial coronary arteries are congested (Figure 2). The liver is enlarged. wvith rounded borders. The parenchvma is hardened and grayish-bro-n. Ascites is a common finding. Interstitial mvocarditis with mononuclear cell infiltration, muscle fiber degeneration s and, in older birds, an endocardial fibroelastosis are reported.5'6 Therefore, Noren et al.7 suggest the RHD of turkeys as a suitable animal model for study of interstitial myocarditis with fibroelastosis in man, as described by Hutchins and Vie.8 Publication sponsored bx- the Registry of Comparativ e Pathology of the Armed Forces Institute of Pathology and supported by Public Health Service Grant RR 00:301 from the Disision of Research Resources. LUS Department of Health. Education and VN elfare. under the auspices of U~nisversities Associated for Research and Education in Pathology. Inc
427
428
NEUMANN ET AL
American Journal of Pathology
--ft;..OOM..,
Figure 1 (left)-Turkey heart showing dilatation of the right ventricle. Figure 2 (rMht)Enlarged heart and
congested subepicar-
dial coronary arteries are seen in this affected turkey heart. -
-7-
Fatty degeneration of liver cells, bile duct proliferation, and nodular mononuclear cell infiltration are generally observed. The liver in older birds display a hvperplastic cirrhosis. The most distinctive lesion is the presence of anhistic intracytoplasmic globules,9 ranging from 2 to 14 g in diameter. The globules appear pink by hematoxylin and eosin staining and give a positive periodic acid-Schiff reaction that is not altered by diastase treatment (Figure 3). By phosphotungstic acid-hematoxylin staining, the globules display a bluish-black color, and the larger globules are surrounded by a clear halo. The globules contain a-globulins as demonstrated by immunofluorescent technique (Figure 4).10 Immunoelectrophoretic analyses of serum sho-w a characteristic aglobulin deficiency in 87%t of affected turkeys (Figure 5)."
q d
Figure 3 (left)-Periodic acid-Schiff-positive intracytoplasmic granules in liver (x 900). Figure 4 (riht)-intracytoplasmic globules which contain a-globulins, as visualized by immunofluorescence technique in liver (x 630).
Vol. 84, No. 2 August 1976
a,-ANTITRYPSIN DEFICIENCY
429
-WW-pal"W.
Fge 5-Disc electrophoresis pattern of turkey sera from normal bird (1) and from turkey with round heart disease, lacking a-globulins (2).
I
2
The trypsin inhibition capacity (TIC) in affected turkeys with RHD is significantly lower than in normal birds. The TIC expressed in milligrams of trypsin inhibited by 1 ml serum in affected turkeys is as follows: 0.655 ± 0.0712 in poults which died with RHD and 0.698 ± 0.0806 in living poults affected with RHD. In the control groups TIC values are: 1.229 ± 0.0487 (t = 6.821, P < 0.001) in the first trial and 1.086 ± 0.126 (t = 2.713, 0.01 < P < 0.025) for the second trial. Turkevs used in each trial were from the same flock and of the same age.12 Comparison Wh a,-Antiftypsin Deficieny
a,-Antitrypsin (AlA) in man is reviewed in all its aspects by Lieberman,13 Kueppers," and Feldmann et al.15 The common features between RHD of turkeys and AlA deficiency in man are the liver lesions and the changes in the blood. In AlA deficiency, identical intracytoplasmic globules are present in liver cells as in RHD of turkeys. In both instances the serum showvs a low antiproteolytic activity. The other cardinal lesions in the two conditions are different, i.e., panemphvsema of the lung in man and heart dilatation in turkeys. In AlA the pathogenesis of the lung emphysema is explained bv the decrease of AlA activity and a subsequent increase in proteolvtic activitv that destrovs the alveolar membrane.13 The pathogenesis of the ventricular dila-
430
NEUMANN ET AL
American Joumal
of Pathology
tation in RHD has not been elucidated, but the same increased proteolytic activity may be involved. a1-Antitrypsin deficiency is a genetically controlled condition, and the genetic aspects of RHD need further investigations. Avaabity
Since Magwood and Bray " reported the first case of RHD in Broad Breasted White turkeys in Canada, the condition has been found in the USA in the above strain 1,S,5,6 and in Nicholas strain.6 We have found the condition in the Nicholas strain, in miniturkeys imported from Holland, and in the BUT strain. Refees 1. Einzig S, Jankus EF, Moller JH: Round heart disease in turkeys: A hemodynamic study. Am j Vet Res 33:557-61, 1972 2. Hunsaker WG, Robertson A, Magwood SE: The effect of round heart disease on the electrocardiogram and heart weight of turkey poults. Poultry Sci 50:1712-1720, 1971 3. Hunsaker WG: Round heart disease in four commercial strains of turkevs. Poultrv Sci 1720-1724, 1971 4. Jankus EF, Good AL: Round heart disease in turkeys. Minn V'et 10:1 1-12, 1970 3. Noren GR, Staley NA, Jankus EF, Stevenson JE: Myocarditis in round heart disease of turkeys: A light and electron microscopic study. Virchows Arch Pathol Anat
352:285-295, 1971 6. Sautter JH, Newman JA, Kleven SH, Larsen CT: Pathogenesis of the round heart svndrome in turkeys. Avian Dis 12:614-628, 1968 Noren GR, Staley NA, Kaplan EL, Jankus EF: An animal model of human disease: Cardiomvopathy. Comp Pathol Bull 6:3-4, 1974 8. Hutchins GM, Vie SA: The progression of interstitial myocarditis to idiopathic endocardial fibroelastosis. Am J Pathol 66:483-496, 1972 9. Neumann F, Klopfer U, Nobel TA, Dison MS, Bendheim U: Peculiar liver changes in round heart disease in turkeys. Vet Rec 98:599-601, 1973 10. Meirom R, Trainin Z, Neumann F, KJopfer U, Dison MS, Rattner D: Alphaglobulin intracytoplasmic hepatocyte globules in round heart disease in turkeys, visualized by inmunofluorescent technique. Poultry Sci 54:1218-1220, 1975 11. Meirom R, Trainin Z, Barnea A, Neumann F, Klopfer U, Nobel TA, Dison NIS, Plesser 0: Hypoproteinemia and alpha globulin deficiency in round heart disease of turkeys. Vet Rec 94:262-264, 1974 12. Rattner D. Deficiency of trypsin-inhibiting capacity in serum of turkeys with round heart disease. J Comp Pathol 86:131-133, 1976 13. Lieberman J: Alpha,-antitr psin deficiency. Med Clin N Am 37:691-706, 1973 14. Kueppers F: Human alpha1-antitrypsin. Environ Res 6:403-423, 1973 15. Feldmann G, Bignon J, Chahinian P: The liver in alpha,-antitrv`psin deficiency. Digestion 10:162-174, 1974 16. Magwood SE, Bray DF: Disease condition of turkeys poults characterized by enlarged hearts. Can J Comp NMed V7et Sci 26:268-272, 1962
