RESUMEN
This case series investigates a cluster of deaths in a captive colony of Leschenault's rousettes (Rousettus leschenaultii). Six of seven bats that died between March and September 2021 were diagnosed postmortem with both iron overload (IO) and neoplasia, neither of which have previously been reported in this species. Iron status was assessed via hepatic histopathological grading, hepatic iron concentration, and, in two cases, serum iron concentration. On histopathological grading, all cases had hemochromatosis except one, which had hemosiderosis. Hepatic iron concentrations did not correlate with histopathological grading. Neoplasms in these six bats included hepatocellular carcinoma (HCC; 4), bronchioloalveolar adenocarcinoma (1), pancreatic adenocarcinoma (1), and sarcoma of the spleen and stomach (1). One bat had two neoplasms (HCC and sarcoma of the spleen and stomach). One additional case of HCC in 2018 was identified on retrospective case review. Etiology was investigated to the extent possible in a clinical setting. Nutritional analysis and drinking water testing found oral iron intake within acceptable bounds; however, dietary vitamin C was potentially excessive and may have contributed to IO. Panhepadnavirus PCR testing of liver tissue was negative for all bats. A species-associated susceptibility to IO, as seen in Egyptian fruit bats (Rousettus aegyptiacus), is possible. The high incidence of HCC is suspected to be related to IO; other differentials include viral infection. Causes or contributing factors were not definitively identified for the other neoplasms seen but could include age, inherited risk (given a high level of inbreeding), or an oncogenic virus. Pending further research in this species, it is recommended that keepers of Leschenault's rousettes offer conservative amounts of vitamin C and iron (as for Egyptian fruit bats), submit for postmortem examination any euthanized or found dead, and share records of similar cases.
Asunto(s)
Adenocarcinoma , Carcinoma Hepatocelular , Quirópteros , Hemocromatosis , Neoplasias Hepáticas , Neoplasias Pancreáticas , Sarcoma , Animales , Adenocarcinoma/veterinaria , Ácido Ascórbico , Carcinoma Hepatocelular/veterinaria , Quirópteros/metabolismo , Hemocromatosis/complicaciones , Hemocromatosis/veterinaria , Neoplasias Hepáticas/veterinaria , Neoplasias Pancreáticas/veterinaria , Estudios Retrospectivos , Sarcoma/veterinariaRESUMEN
After an Egyptian fruit bat (Rousettus aegyptiacus) in a zoo became emaciated and died, a necropsy revealed multiple nodules on the liver and lung surfaces. Microscopy revealed that the liver nodules consisted of neoplastic hepatocytes and showed metastasis in the lung lobes. Most of the neoplastic cells in the liver and lung showed positive labeling for HepPar-1, cytokeratin 19, glypican-3, and Ki-67. Hepatocellular degeneration and necrosis were diffuse in the liver parenchyma. Berlin blue staining revealed large amounts of iron in normal and neoplastic cells. Based on these pieces of evidence, this case was diagnosed as hepatocellular carcinoma with hemochromatosis. This is believed to be the first report of hepatocellular carcinoma in an Egyptian fruit bat that has been immunophenotypically examined in detail by pathological examination.
Asunto(s)
Carcinoma Hepatocelular , Quirópteros , Hemocromatosis , Neoplasias Hepáticas , Neoplasias Pulmonares , Animales , Hemocromatosis/veterinaria , Carcinoma Hepatocelular/veterinaria , Neoplasias Hepáticas/veterinaria , Neoplasias Pulmonares/veterinariaRESUMEN
A 14-year-old, male sugar glider presented with lethargy, anorexia, diarrhea, and paralysis of the hind limbs, and ultrasonography showed possible liver dysfunction. Some medications were administered, but the animal died 10 months after the first presentation, and a necropsy was performed. Histopathologically, hepatocellular degeneration and necrosis, severe deposition of hemosiderin in Kupffer cells and hepatocytes, bridging fibrosis, and regenerative nodules were observed in the liver. Variably amounts of hemosiderin deposition was observed in the heart, lungs, spleen, and kidney. These findings led to the diagnosis of hemochromatosis. No sugar glider cases with hemochromatosis have been reported. The pathological characteristics of hemochromatosis in this species were documented for the first time. The pathogenesis of hemochromatosis in animals remains unclear, but it has been suggested that some commercially available food for sugar gliders containing excessive amounts of iron and vitamin C may induce the disease.
Asunto(s)
Hemocromatosis , Marsupiales , Animales , Masculino , Hemocromatosis/diagnóstico , Hemocromatosis/veterinaria , HemosiderinaRESUMEN
Some wild species of mammals and birds are prone to excessive iron accumulation, especially when maintained in human care. Hemosiderosis is the process of intracellular accumulation of iron without evidence of toxicity, whereas hemochromatosis is characterized by severe iron accumulation with accompanying organ damage. Iron storage disease (ISD) occurs when organ damage is severe and causing clinical signs. This retrospective study investigated the occurrence of hemosiderosis and ISD across a variety of avian taxa, including captive and free-ranging birds. Archived paraffin-embedded hepatic samples from 103 birds from Belo Horizonte Zoo that died naturally in the period of 2008 to 2018 were re-evaluated with histologic and morphometric techniques, focusing on the identification and scoring of iron deposits in hepatocytes and the quantification of total affected hepatic area. The birds represented 13 orders, 22 families, and 52 genera, and 66 (64.0%) had some degree of iron accumulation in their liver. Importantly, no statistical difference was observed in the occurrence of iron accumulation between families, orders, or origin (free-ranging or captive). Direct and positive correlation was observed between the total area affected by the iron deposits and the histologic score. In this study, there were two cases with severe iron accumulation and clinical signs compatible with ISD: a barefaced curassow (Crax fasciolata) and a channel-billed toucan (Ramphastos vitellinus). This study indicates that iron accumulation may occur in a wide range of avian species, with frequencies and intensities that are similar between free-ranging birds and those in human care. It describes for the first time the occurrence of ISD in a Galliform species.
Asunto(s)
Enfermedades de las Aves , Hemocromatosis , Hemosiderosis , Animales , Animales Salvajes , Animales de Zoológico , Enfermedades de las Aves/epidemiología , Aves , Hemocromatosis/epidemiología , Hemocromatosis/veterinaria , Hemosiderosis/epidemiología , Hemosiderosis/veterinaria , Estudios RetrospectivosAsunto(s)
Hemocromatosis , Enfermedades de los Caballos , Animales , Biopsia/veterinaria , Hemocromatosis/diagnóstico , Hemocromatosis/patología , Hemocromatosis/veterinaria , Hepatomegalia/patología , Hepatomegalia/veterinaria , Enfermedades de los Caballos/diagnóstico , Enfermedades de los Caballos/patología , Caballos , Hígado/patologíaRESUMEN
This report describes hemochromatosis associated with chronic parenteral iron dextran administration in 2 female olive baboons (Papio anubis). These baboons were enrolled on an experimental protocol that induced and maintained anemia by periodic phlebotomy for use in studying potential treatments for sickle cell anemia. The 2 baboons both presented with clinical signs consistent with iron overload, including decreased appetite, weight loss, elevated liver enzymes, and hepatosplenomegaly. Histopathologic findings supported a morphologic diagnosis of systemic hemosiderosis, as evidenced by the overwhelming presence of iron in the reticuloendothelial system and liver after the application of Prussian blue stain. This finding, combined with the clinical presentation, lead to a final diagnosis of hemochromatosis. This case report suggests that providing anemic patients with chronic parenteral iron supplementation in the absence of iron deficiency can result in iatrogenic iron overload and subsequent systemic toxicity. Furthermore, these subjects may present with hemochromatosis and its associated clinical signs many years after cessation of iron supplementation.
Asunto(s)
Hemocromatosis , Hemosiderosis , Animales , Femenino , Hemocromatosis/diagnóstico , Hemocromatosis/veterinaria , Hemosiderosis/inducido químicamente , Hemosiderosis/veterinaria , Humanos , Hierro , Papio , Papio anubis , Flebotomía/veterinariaRESUMEN
Sloths are xenarthrans from Central and South America with a highly adapted morphophysiology. Five of the six known species of sloths are found in Brazil, among which Bradypus torquatus (maned three-toed sloth) is considered a vulnerable species by International Union for Conservation of Nature. Nevertheless, knowledge on health and disease of sloths is very scarce, thus this study aimed to describe macroscopic and microscopic findings in 36 Brazilian sloths. The most common findings included iron storage disorder, probable bacterial pneumonia, gastric and intestinal nematode parasitism, and a presumptive diagnosis of systemic mastocytosis.
Asunto(s)
Enfermedades Gastrointestinales/veterinaria , Hemocromatosis/veterinaria , Mastocitosis Sistémica/veterinaria , Nematodos/aislamiento & purificación , Neumonía Bacteriana/veterinaria , Perezosos , Animales , Brasil/epidemiología , Enfermedades Gastrointestinales/parasitología , Enfermedades Gastrointestinales/patología , Hemocromatosis/epidemiología , Hemocromatosis/patología , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/patología , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/patologíaRESUMEN
Hepcidin is the key regulator of iron homeostasis in the body. Iron storage disease (hemochromatosis) is a frequent cause of liver disease and mortality in captive Egyptian fruit bats (Rousettus aegyptiacus), but reasons underlying this condition are unknown. Hereditary hemochromatosis in humans is due to deficiency of hepcidin or resistance to the action of hepcidin. Here, we investigated the role of hepcidin in iron metabolism in one species of pteropodid bat that is prone to iron storage disease [Egyptian fruit bat (with and without hemochromatosis)], one species of pteropodid bat where iron storage disease is rare [straw-colored fruit bat (Eidolon helvum)], and one species of bat with a natural diet very high in iron, in which iron storage disease is not reported [common vampire bat (Desmodus rotundus)]. Iron challenge via intramuscular injection of iron dextran resulted in significantly increased liver iron content and histologic iron scores in all three species, and increased plasma iron in Egyptian fruit bats and straw-colored fruit bats. Hepcidin mRNA expression increased in response to iron administration in healthy Egyptian fruit bats and common vampire bats, but not in straw-colored fruit bats or Egyptian fruit bats with hemochromatosis. Hepcidin gene expression significantly correlated with liver iron content in Egyptian fruit bats and common vampire bats, and with transferrin saturation and plasma ferritin concentration in Egyptian fruit bats. Induction of hepcidin gene expression in response to iron challenge is absent in straw-colored fruit bats and in Egyptian fruit bats with hemochromatosis and, relative to common vampire bats and healthy humans, is low in Egyptain fruit bats without hemochromatosis. Limited hepcidin response to iron challenge may contribute to the increased susceptibility of Egyptian fruit bats to iron storage disease.
Asunto(s)
Quirópteros/metabolismo , Hemocromatosis/metabolismo , Hepcidinas/genética , Complejo Hierro-Dextran/farmacología , Hierro/metabolismo , Hígado/efectos de los fármacos , Animales , Femenino , Hemocromatosis/veterinaria , Hígado/metabolismo , MasculinoRESUMEN
Within a 2-wk period, three African grey parrots ( Psittacus erithacus) presented for emergency treatment. All three parrots had depressed behavior, an inability to fly, and significant weight loss. Plasma chemistry abnormalities included severe hypoproteinemia and elevated liver enzymes in all parrots. Two of the parrots died, and histologic examination with hematoxylin and eosin and Prussian blue stains revealed severe hepatic iron storage. Quantitative analysis confirmed high hepatic iron concentrations. Iron accumulation was attributed to ingestion of a carnivorous bird diet or selectively eating too much fruit and vegetables high in ascorbic acid. Management entailed husbandry changes including switching the remaining parrots to a low-iron diet. Psittacine species exposed to carnivorous bird diets are at risk of developing iron storage disease.
Asunto(s)
Alimentación Animal/análisis , Enfermedades de las Aves/etiología , Dieta/veterinaria , Hemocromatosis/veterinaria , Hierro/efectos adversos , Loros , Animales , Enfermedades de las Aves/patología , Resultado Fatal , Femenino , Hemocromatosis/etiología , Hemocromatosis/patología , Hierro/administración & dosificación , MasculinoRESUMEN
The aim of this study was to determine if ferritin is a reliable biomarker of iron overload disorder (IOD) progression and hemochromatosis in the Sumatran rhinoceros (Dicerorhinus sumatrensis) by developing a species-specific ferritin assay and testing historically banked samples collected from rhinos that did and did not die of hemochromatosis. Ferritin extracted from Sumatran rhino liver tissue was used to generate antibodies for the Enzyme Immunoassay. Historically banked Sumatran rhino serum samples (n = 298) obtained from six rhinos in US zoos (n = 290); five rhinos at the Sumatran Rhino Conservation Centre in Sungai Dusun, Malaysia (n = 5); and two rhinos in Sabah, Malaysia (n = 3) were analyzed for ferritin concentrations. Across all US zoo samples, serum ferritin concentrations ranged from 348 to 7,071 ng/ml, with individual means ranging from 1,267 (n = 25) to 2,604 ng/ml (n = 36). The ferritin profiles were dynamic, and all rhinos exhibited spikes in ferritin above baseline during the sampling period. The rhino with the highest mean ferritin concentration did not die of hemochromatosis and exhibited only mild hemosiderosis postmortem. A reproductive female exhibited decreases and increases in serum ferritin concurrent with pregnant and nonpregnant states, respectively. Mean (±SD) serum ferritin concentration for Sumatran rhinos in Malaysia was high (4,904 ± 4,828 ng/ml) compared to that for US zoo rhinos (1,835 ± 495 ng/ml). However, those in Sabah had lower ferritin concentrations (1,025 ± 52.7 ng/ml) compared to those in Sungai Dusun (6,456 ± 4,941 ng/ml). In conclusion, Sumatran rhino serum ferritin concentrations are dynamic, and increases often are not associated with illness or hemochromatosis. Neither a specific pattern nor the individual's overall mean ferritin concentration can be used to accurately assess IOD progression or diagnose hemochromatosis in this rhino species.
Asunto(s)
Ferritinas/sangre , Hemocromatosis/veterinaria , Sobrecarga de Hierro/veterinaria , Perisodáctilos/sangre , Animales , Biomarcadores/sangre , Femenino , Hemocromatosis/sangre , Sobrecarga de Hierro/sangre , Hígado/química , Masculino , Reproducibilidad de los Resultados , Especificidad de la EspecieRESUMEN
A variety of wildlife species maintained in captivity are susceptible to iron storage disease (ISD), or hemochromatosis, a disease resulting from the deposition of excess iron into insoluble iron clusters in soft tissue. Sumatran rhinoceros (Dicerorhinus sumatrensis) is one of the rhinoceros species that has evolutionarily adapted to a low-iron diet and is susceptible to iron overload. Hemosiderosis is reported at necropsy in many African black and Sumatran rhinoceroses but only a small number of animals reportedly die from hemochromatosis. The underlying cause and reasons for differences in susceptibility to hemochromatosis within the taxon remains unclear. Although serum ferritin concentrations have been useful in monitoring the progression of ISD in many species, there is some question regarding their value in diagnosing hemochromatosis in the Sumatran rhino. To investigate the metabolic changes during the development of hemochromatosis and possibly increase our understanding of its progression and individual susceptibility differences, the serum metabolome from a Sumatran rhinoceros was investigated by nuclear magnetic resonance (NMR)-based metabolomics. The study involved samples from female rhinoceros at the Cincinnati Zoo (n = 3), including two animals that died from liver failure caused by ISD, and the Sungai Dusun Rhinoceros Conservation Centre in Peninsular Malaysia (n = 4). Principal component analysis was performed to visually and statistically compare the metabolic profiles of the healthy animals. The results indicated that significant differences were present between the animals at the zoo and the animals in the conservation center. A comparison of the 43 serum metabolomes of three zoo rhinoceros showed two distinct groupings, healthy (n = 30) and unhealthy (n = 13). A total of eighteen altered metabolites were identified in healthy versus unhealthy samples. Results strongly suggest that NMR-based metabolomics is a valuable tool for animal health monitoring and may provide insight into the progression of this and other insidious diseases.
Asunto(s)
Hemocromatosis/veterinaria , Metabolómica , Perisodáctilos/metabolismo , Animales , Estudios de Casos y Controles , Progresión de la Enfermedad , Estudios de Factibilidad , Hemocromatosis/sangre , Hemocromatosis/metabolismo , Espectroscopía de Resonancia Magnética , Perisodáctilos/sangreRESUMEN
Egyptian fruit bats (Rousettus aegyptiacus) are one of many species within zoologic collections that frequently develop iron storage disease. The goals of this retrospective multi-institutional study were to determine the tissue distribution of iron storage in captive adult Egyptian fruit bats and the incidence of intercurrent neoplasia and infection, which may be directly or indirectly related to iron overload. Tissue sections from 83 adult Egyptian fruit bats were histologically evaluated by using tissue sections stained with hematoxylin and eosin, trichrome, and Prussian blue techniques. The liver and spleen consistently had the largest amount of iron, but significant amounts of iron were also detected in the pancreas, kidney, skeletal muscle, and lung. Hepatocellular carcinoma (HCC; 11) was the most common neoplasm, followed by cholangiocarcinoma (4). Extrahepatic neoplasms included bronchioloalveolar adenoma (3), pulmonary carcinosarcoma (1), oral sarcoma (1), renal adenocarcinoma (1), transitional cell carcinoma of the urinary bladder (1), mammary gland adenoma (1), and parathyroid adenoma (1). There were also metastatic neoplasms of undetermined primary origin that included three poorly differentiated carcinomas, a poorly differentiated sarcoma, and a neuroendocrine tumor. Bats with hemochromatosis were significantly more likely to have HCC than bats with hemosiderosis (P = 0.032). Cardiomyopathy was identified in 35/77 bats with evaluable heart tissue, but no direct association was found between cardiac damage and the amount of iron observed within the liver or heart. Hepatic abscesses occurred in multiple bats, although a significant association was not observed between hemochromatosis and bacterial infection. To the authors' knowledge, this is the first publication providing evidence of a positive correlation between hemochromatosis and HCC in any species other than humans.
Asunto(s)
Quirópteros , Hemocromatosis/veterinaria , Animales , Animales de Zoológico , Hemocromatosis/patología , Estudios RetrospectivosRESUMEN
Hemochromatosis (iron storage disease) has been reported in diverse mammals including bottlenose dolphins (Tursiops truncatus). The primary cause of excessive iron storage in humans is hereditary hemochromatosis. Most human hereditary hemochromatosis cases (up to 90%) are caused by a point mutation in the hfe gene, resulting in a C282Y substitution leading to iron accumulation. To evaluate the possibility of a hereditary hemochromatosis-like genetic predisposition in dolphins, we sequenced the bottlenose dolphin hfe gene, using reverse transcriptase-PCR and hfe primers designed from the dolphin genome, from liver of affected and healthy control dolphins. Sample size included two case animals and five control animals. Although isotype diversity was evident, no coding differences were identified in the hfe gene between any of the animals examined. Because our sample size was small, we cannot exclude the possibility that hemochromatosis in dolphins is due to a coding mutation in the hfe gene. Other potential causes of hemochromatosis, including mutations in different genes, diet, primary liver disease, and insulin resistance, should be evaluated.
Asunto(s)
Delfín Mular/genética , Predisposición Genética a la Enfermedad , Hemocromatosis/veterinaria , Antígenos de Histocompatibilidad Clase I/metabolismo , Empalme Alternativo , Animales , Estudios de Casos y Controles , Variación Genética , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Iron overload is common in lemurs and some New World nonhuman primates raised in captivity, but there is no such documentation in the red bald-headed uakari (Cacajao calvus rubicundus). This study describes postmortem documentation of severe iron storage disease in one red bald-headed uakari and the use of iron chelation with oral deferasirox in the three surviving members of the colony. Magnetic resonance imaging was used to quantify pretreatment iron burden and to follow the response to therapy in two females, 22 and 28 yr of age, and one male 33 yr of age. Baseline liver iron concentrations ranged from 16 to 23 mg/g dry weight. In humans, a liver iron concentration greater than 15 mg/g is considered severe and associated with endocrine and cardiac toxicity. The uakaris were otherwise asymptomatic, generally healthy, nonpregnant, and on a stable, low-iron diet. Quantitative magnetic resonance imaging indicated that dosage escalations up to 100 mg/kg were needed to produce meaningful reductions in iron stores. After 5 yr of therapy, two animals continue at a dosage of 100 mg/kg per day, and the third was transitioned to twice-weekly maintenance dosing because of successful de-ironing. The animals tolerated iron chelation therapy well, having stable hematologic, renal, and hepatic function profiles before, during, and after treatment. Deferasirox monotherapy may represent a therapeutic option in primates with iron storage disease when dietary measures are ineffective and phlebotomy is logistically challenging.
Asunto(s)
Benzoatos/uso terapéutico , Hemocromatosis/veterinaria , Quelantes del Hierro/uso terapéutico , Enfermedades de los Monos/tratamiento farmacológico , Pitheciidae , Triazoles/uso terapéutico , Animales , Benzoatos/administración & dosificación , Deferasirox , Femenino , Hemocromatosis/tratamiento farmacológico , Quelantes del Hierro/administración & dosificación , Masculino , Triazoles/administración & dosificaciónRESUMEN
A widespread deadly outbreak occurred in captive birds belonging to the family Turdidae in Italy. The present study was performed on 46 dead birds coming from 3 small decoy-bird breeders in central Italy. Only Turdus pilaris, Turdus iliacus, Turdus philomelos and Turdus merula were affected. No other species of bird held by these breeders died. A change of diet before the hunting season was reported from all breeders. Full necropsy of the animals and histological investigations of representative tissue samples were performed. Microscopical examination showed marked iron deposits in liver samples. Bacteriological investigations and molecular analysis to exclude bacterial and viral diseases were carried out. Contamination of food pellet samples by mycotoxins and analysis to detect heavy metal contaminants in food pellet samples were considered. An interesting result was the high iron content found in food pellets. It was higher than that considered suitable for birds, especially for species susceptible to development iron storage disease (ISD). Taken together, the results suggested an outbreak of ISD caused by the high iron content of food given to the birds before the hunting season. The high mortality recorded only in species belonging to the family Turdidae suggests a genetic predisposition in the affected birds.
Asunto(s)
Alimentación Animal/toxicidad , Enfermedades de las Aves/metabolismo , Brotes de Enfermedades/veterinaria , Hemocromatosis/veterinaria , Hepatopatías/veterinaria , Pájaros Cantores , Animales , Enfermedades de las Aves/epidemiología , Femenino , Hemocromatosis/epidemiología , Hemocromatosis/metabolismo , Histocitoquímica/veterinaria , Italia/epidemiología , Hepatopatías/epidemiología , Hepatopatías/metabolismo , Masculino , Estaciones del AñoRESUMEN
Hemochromatosis, or iron storage disease, has been associated with significant liver disease and mortality in captive Egyptian fruit bats (Rousettus aegyptiacus). The physiologic basis for this susceptibility has not been established. In humans, a deficiency or resistance to the iron regulatory hormone, hepcidin has been implicated in the development of hereditary hemochromatosis. In the present study, we compared the coding sequence of the hepcidin gene in eight species of bats representing three distinct taxonomic families with diverse life histories and dietary preferences. Bat hepcidin mRNA encoded a 23 amino acid signal peptide, a 34 or 35 amino acid pro-region, and a 25 amino acid mature peptide, similar to other mammalian species. Differences in the sequence of the portion of the hepcidin gene that encodes the mature peptide that might account for the increased susceptibility of the Egyptian fruit bat to iron storage disease were not identified. Variability in gene sequence corresponded to the taxonomic relationship amongst species.
Asunto(s)
Quirópteros/metabolismo , Variación Genética/fisiología , Hemocromatosis/veterinaria , Hepcidinas/metabolismo , Filogenia , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Quirópteros/genética , ADN/química , ADN/genética , Predisposición Genética a la Enfermedad , Variación Genética/genética , Hemocromatosis/genética , Hemocromatosis/metabolismo , Hepcidinas/genética , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa/veterinaria , Alineación de Secuencia , Análisis de Secuencia de ADNRESUMEN
Disorders of iron metabolism are among the most common acquired and constitutive diseases. Hemochromatosis has a solid genetic basis and in Northern European populations it is usually associated with homozygosity for the C282Y mutation in the HFE protein. However, the penetrance of this mutation is incomplete and the clinical presentation is highly variable. The rare and common variants identified so far as genetic modifiers of HFE-related hemochromatosis are unable to account for the phenotypic heterogeneity of this disorder. There are wide variations in the basal iron status of common inbred mouse strains, and this diversity may reflect the genetic background of the phenotypic diversity under pathological conditions. We therefore examined the genetic basis of iron homeostasis using quantitative trait loci mapping applied to the HcB-15 recombinant congenic strains for tissue and serum iron indices. Two highly significant QTL containing either the N374S Mon1a mutation or the Ferroportin locus were found to be major determinants in spleen and liver iron loading. Interestingly, when considering possible epistatic interactions, the effects of Mon1a on macrophage iron export are conditioned by the genotype at the Slc40a1 locus. Only mice that are C57BL/10ScSnA homozygous at both loci display a lower spleen iron burden. Furthermore, the liver-iron lowering effect of the N374S Mon1a mutation is observed only in mice that display a nonsense mutation in the Ceruloplasmin (Cp) gene. This study highlights the existence of genetic interactions between Cp, Mon1a, and the Slc40a1 locus in iron metabolism, suggesting that epistasis may be a crucial determinant of the variable biological and clinical presentations in iron disorders.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Transporte de Catión/genética , Ceruloplasmina/genética , Epistasis Genética , Hemocromatosis/veterinaria , Hierro/metabolismo , Ratones/genética , Enfermedades de los Roedores/genética , Animales , Femenino , Hemocromatosis/genética , Hemocromatosis/metabolismo , Hígado/metabolismo , Masculino , Ratones/metabolismo , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Sitios de Carácter Cuantitativo , Enfermedades de los Roedores/metabolismo , Bazo/metabolismoRESUMEN
UNLABELLED: Hemochromatosis in bottlenose dolphins (Tursiops truncatus) is associated with high postprandial plasma insulin levels, suggestive of insulin resistance. In humans, insulin resistance is associated with liver pathologies, including excessive iron deposition and nonalcoholic fatty liver disease. Dolphin liver tissues, in addition to excessive iron storage, were evaluated for other pathologies supportive of underlying insulin resistance. Archived liver tissues collected postmortem during 1985-2010 from 18 dolphins (median age 27.9 yr, range 0.7-51.4) that were part of the Navy Marine Mammal Program's managed collection were assessed for the presence and severity of hemosiderin deposition, fatty liver disease, and hepatitis. Demographics, clinical pathology values, and percentage weight loss were compared among dolphins with and without these changes. Twelve (66.7%) dolphins had mild to moderate hemosiderin deposition, 7 (38.9%) had mild to severe fatty liver disease, and 11 (61.1%) had mild to moderate hepatitis. Of the 12 dolphins with hemosiderosis, deposition occurred in the Kupffer cells among 11 (91.7%). Dolphins with fatty liver disease were more likely to have higher postprandial serum hyperglycemia (>140 mg/dl), leukocytosis (>11,000 cells/microl), and hyperglobulinemia (>3.5 g/dl). Unlike in many nonhuman terrestrial animals, fatty liver disease was not associated with rapid weight loss or hypoglycemia. Interestingly, there were no significant associations among dolphins with hemosiderosis, fatty liver disease, and hepatitis. This study supports that both hemochromatosis and fatty liver disease were present in the dolphin study population, and histopathology and clinical pathology among these animals suggest a nonhereditary, metabolic etiology. KEYWORDS: Bottlenose dolphin, fatty liver disease, hemochromatosis, hemosiderosis, hepatic lipidosis, hepatitis, Tursiops truncatus.
Asunto(s)
Delfín Mular , Hígado Graso/veterinaria , Hemocromatosis/veterinaria , Resistencia a la Insulina/fisiología , Animales , Hígado Graso/metabolismo , Hígado Graso/patología , Hemocromatosis/metabolismo , Hemocromatosis/patología , Hiperglucemia/veterinaria , Inflamación/patología , Inflamación/veterinaria , Macrófagos del Hígado , Factores de RiesgoRESUMEN
BACKGROUND: Erythrocytic pyruvate kinase (PK) deficiency, first documented in Basenjis, is the most common inherited erythroenzymopathy in dogs. OBJECTIVES: To report 3 new breed-specific PK-LR gene mutations and a retrospective survey of PK mutations in as mall and selected group of Beagles and West Highland White Terriers (WHWT). ANIMALS: Labrador Retrievers (2 siblings, 5 unrelated), Pugs (2 siblings, 1 unrelated), Beagles (39 anemic, 29 other),WHWTs (22 anemic, 226 nonanemic), Cairn Terrier (n = 1). METHODS: Exons of the PK-LR gene were sequenced from genomic DNA of young dogs (<2 years) with persistent highly regenerative hemolytic anemia. RESULTS: A nonsense mutation (c.799C>T) resulting in a premature stop codon was identified in anemic Labrador Retriever siblings that had osteosclerosis, high serum ferritin concentrations, and severe hepatic secondary hemochromatosis. Anemic Pug and Beagle revealed 2 different missense mutations (c.848T>C, c.994G>A, respectively) resulting in intolerable amino acid changes to protein structure and enzyme function. Breed-specific mutation tests were developed. Among the biased group of 248 WHWTs, 9% and 35% were homozygous (affected) and heterozygous, respectively, for the previously described mutation (mutant allele frequency 0.26). A PK-deficient Cairn Terrier had the same insertion mutation as the affected WHWTs. Of the selected group of 68 Beagles, 35% were PK-deficient and 3% were carriers (0.37). CONCLUSIONS AND CLINICAL IMPORTANCE: Erythrocytic PK deficiency is caused by different mutations in different dog breeds and causes chronic severe hemolytic anemia, hemosiderosis, and secondary hemochromatosis because of chronic hemolysis and, an as yet unexplained osteosclerosis. The newly developed breed-specific mutation assays simplify the diagnosis of PK deficiency.
Asunto(s)
Anemia Hemolítica/veterinaria , Enfermedades de los Perros/genética , Eritrocitos/enzimología , Hemocromatosis/veterinaria , Mutación , Osteosclerosis/veterinaria , Piruvato Quinasa/genética , Secuencia de Aminoácidos , Anemia Hemolítica/enzimología , Anemia Hemolítica/genética , Animales , Secuencia de Bases , Codón sin Sentido , Enfermedades de los Perros/sangre , Enfermedades de los Perros/enzimología , Perros , Femenino , Hemocromatosis/sangre , Hemocromatosis/enzimología , Hemocromatosis/genética , Masculino , Datos de Secuencia Molecular , Mutación Missense , Osteosclerosis/sangre , Osteosclerosis/enzimología , Osteosclerosis/genética , Piruvato Quinasa/deficienciaRESUMEN
A 23-year-old Brazilian, or lowland, tapir with a 6-month history of loss of body condition developed clinical signs and laboratory findings consistent with liver failure. The animal was euthanased and a diagnosis of hepatic haemochromatosis was made based on histopathology. Two other healthy tapirs in the same collection had chronically elevated serum and tissue iron concentrations. The excessive accumulation of iron in tissues with resultant tissue damage (i.e. haemochromatosis) has been reported in a range of captive species. This and other reported cases of haemochromatosis in the Brazilian tapir would suggest that this condition is an important consideration in the management of this species in zoos. Further research into the endogenous regulation of iron metabolism, especially the role of hepcidin, in tapirs and other species at risk of iron storage disorders may be helpful in the prevention of this condition.