Iron Storage Disease Research Articles

USE OF VISCOELASTIC COAGULATION TESTING IN MEGACHIROPTERA (PTEROPUS HYPOMELANUS AND PTEROPUS VAMPYRUS) REVEALS HIGH VARIABILITY IN CLOT KINETICS.

Megachiroptera is a mammalian suborder that includes old world fruit bats. Common clinical problems among captive Megachiroptera, such as liver disease (e.g., iron storage disease), kidney disease (e.g., protein-losing nephropathy), and heart disease (e.g., dilated cardiomyopathy), carry elevated risk for hemostatic derangements. The assessment of viscoelastic coagulation assays, however, has not yet been reported in bats. The main objective of the study was to describe viscoelastography data using the Viscoelastic Coagulation Monitor (VCM) Vet in captive large flying foxes (Pteropus vampyrus) (n = 20) and variable flying foxes (Pteropus hypomelanus) (n = 10). Additional objectives were to compare viscoelastic and clotting parameters (1) between healthy P. vampyrus and P. hypomelanus bats and (2) between untreated bats and those treated with meloxicam or aspirin, and (3) to examine relationships between activated partial thromboplastin time (aPTT) and potentially homologous viscoelastic parameters clotting time (CT) and clot formation time (CFT). The results showed marked variability among clinically normal bats. The intrinsic pathway, as measured by aPTT, had prolonged times compared with most terrestrial mammals, but similar times to birds, marine mammals, and sea turtles. A search of P. vampyrus genome found stop codons present in two exons of the factor XI gene; alterations in factor XI expression would be expected to alter intrinsic coagulation. Because of the high variability, no statistically significant findings were noted in the secondary objectives. Correlation between aPTT and CT or CFT was not strong (rs = 0.406 or 0.192, respectively). The results from this study suggest that clot kinetics vary widely among Megachiroptera when using the VCM Vet with untreated blood. A prolonged intrinsic coagulation pathway, as has been found in other megachiropteran species, and activation of the extrinsic coagulation pathway during venipuncture may be responsible for the inconsistent results.

A RETROSPECTIVE STUDY OF HEPATIC HEMOSIDEROSIS AND IRON STORAGE DISEASE IN SEVERAL CAPTIVE AND FREE-RANGING AVIAN SPECIES.

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.

Hepatic lesions associated with iron accumulation in captive kori bustards (Ardeotis kori).

There are anecdotal reports of iron storage disease in captive kori bustards (Ardeotis kori), but detailed descriptions of this disease have not been reported. The goals of this retrospective, multi-institutional study were to (1) describe microscopic findings associated with iron accumulation in postmortem tissues of kori bustards and (2) use an adapted grading scale to score iron accumulation and associated hepatic lesions. Tissue sections from 19 adult captive kori bustards (age range 3-28 years; 12 males and 7 females) were evaluated histologically with hematoxylin and eosin, Masson's trichrome, and Prussian blue stains, and scored for iron accumulation. Hemochromatosis was diagnosed in cases with iron storage (in hepatocytes and/or Kupffer cells) and concurrent parenchymal damage (defined as having both necrosis and fibrosis). Hemosiderosis was diagnosed in animals with evidence of iron storage without necrosis or fibrosis. Ten of the 19 cases (age range 8-27 years; 7 males and 3 females) were diagnosed with hemochromatosis, including 6 with mild disease, 3 with moderate disease, and 1 with severe disease. Histologic evidence of iron accumulation was also identified in kidney, intestinal tract, adrenal gland, and spleen, but there were no associations between severity of iron accumulation in the liver and accumulation in other organs.

MRI-Based Iron Phenotyping and Patient Selection for Next-Generation Sequencing of Non-Homeostatic Iron Regulator Hemochromatosis Genes.

Background and AimsHigh serum ferritin is frequent among patients with chronic liver disease and commonly associated with hepatic iron overload. Genetic causes of high liver iron include homozygosity for the p.Cys282Tyr variant in homeostatic iron regulator (HFE) and rare variants in non‐HFE genes. The aims of the present study were to describe the landscape and frequency of mutations in hemochromatosis genes and determine whether patient selection by noninvasive hepatic iron quantification using MRI improves the diagnostic yield of next‐generation sequencing (NGS) in patients with hyperferritinemia.Approach and ResultsA cohort of 410 unselected liver clinic patients with high serum ferritin (defined as ≥200 μg/L for women and ≥300 μg/L for men) was investigated by HFE genotyping and abdominal MRI R2*. Forty‐one (10%) patients were homozygous for the p.Cys282Tyr variant in HFE. Of the remaining 369 patients, 256 (69%) had high transferrin saturation (TSAT; ≥45%) and 199 (53%) had confirmed hepatic iron overload (liver R2* ≥70 s−1). NGS of hemochromatosis genes was carried out in 180 patients with hepatic iron overload, and likely pathogenic variants were identified in 68 of 180 (38%) patients, mainly in HFE (79%), ceruloplasmin (25%), and transferrin receptor 2 (19%). Low spleen iron (R2* <50 s−1), but not TSAT, was significantly associated with the presence of mutations. In 167 patients (93%), no monogenic cause of hepatic iron overload could be identified.ConclusionsIn patients without homozygosity for p.Cys282Tyr, coincident pathogenic variants in HFE and non‐HFE genes could explain hyperferritinemia with hepatic iron overload in a subset of patients. Unlike HFE hemochromatosis, this type of polygenic hepatic iron overload presents with variable TSAT. High ferritin in blood is an indicator of the iron storage disease, hemochromatosis. A simple genetic test establishes this diagnosis in the majority of patients affected. MRI of the abdomen can guide further genetic testing.

Comparison of iron chelators used alone or in combination with phlebotomy in common mynahs (Acridotheres tristis) with experimental iron storage disease

ABSTRACT To compare the therapeutic effects of iron chelators used alone or in combination with phlebotomy on iron storage disease (ISD), 66 healthy common mynahs (Acridotheres tristis) were fed an iron-loading diet (3000 ppm) for 30 days. After confirmation of ISD, the birds were randomly divided into four treatment groups; DFO: deferoxamine (100 mg/kg SC q24 h), DFP: deferiprone (oral, 75 mg/kg), DFO + F: deferoxamine (100 mg/kg SC q24 h) with phlebotomy, and DFP + F: deferiprone (oral, 75 mg/kg) with phlebotomy. In phlebotomy-treated groups, blood sampling (1% BW) was performed weekly. At 1 and 2 months after treatments, seven birds from each group were euthanized and liver iron, copper, and zinc were analysed by ICP-OES assay. After 1 month, in all treatments, the liver amount of iron, copper, and zinc was reduced (P < 0.05) and there was no significant difference between groups. In the second month, the amount of liver iron, copper, and zinc decreased more in all groups, but this change was insignificant except in the DFP + F group (P < 0.05). These results suggest that all therapeutic protocols after 1 month effectively reduce the liver iron and there is no need to continue treatment. Otherwise, it may lead to iron deficiency, especially in birds treated with DFP + P. Since deferiprone, as an inexpensive oral chelator, effectively reduces liver iron levels without causing stress in the birds, it can be recommended as a more appropriate method for the treatment of mynahs with ISD. However, further clinical studies are needed to define the most effective treatment. RESEARCH HIGHLIGHTS Deferiprone is an optimized method for treating iron storage disease. The essential metals homeostasis is impaired in iron storage disease.

Whole-body R2∗ mapping to quantify tissue iron in iron storage organs: reference values and a genotype

To define reference values for the transverse relaxation rate (R2∗) in iron storage organs and to investigate the role of human haemochromatosis protein (HFE) genotype on iron storage. Whole-body magnetic resonance imaging (MRI) including a five-echo gradient-echo sequence was performed in 483 volunteers (269 men, mean age 59.3±12.2 years) without clinical evidence of an iron storage disease at 1.5 T. R2∗ values were assessed for liver, spleen, pancreas, heart, bones, and brain parenchyma. The HFE genotype was determined regarding the single nucleotide polymorphisms (SNPs) rs74315324, rs1799945, rs41303501, rs1800562, rs1800730. R2∗ values were compared among participants without and with at least one mutation. R2∗ reference values were defined using volunteers without any mutation. Three hundred and one participants had no mutations in any HFE SNP, 182 had at least one mutation. HFE gene mutations were distributed as (heterozygous/homozygous) rs1799945:132/9, rs1800562:33/1, and rs1800730:11/0. Mean R2∗ values±SD (per second) in the group without mutation were: liver: 33.4±12.7, spleen: 24.1±13.8, pancreas: 27.2±6.6, heart: 32.7±11.8, bone: 69.3±21.0, brain parenchyma: 13.9±1.2. No significant difference in R2∗ values were found between participants with and without the HFE gene mutation for any examined iron storage organ (pliver=0.09, pspleen=0.36, ppancreas=0.08, pheart=0.36, pbone=0.98, pbrain=0.74). Reference values of R2∗ in iron storage organs are feasible to support the diagnosis of iron storage diseases. Non-specific mutations in HFE SNPs appear not to affect the phenotype of tissue iron accumulation.

Pathology of Free-Ranging and Captive Brazilian Anteaters

There is little information on the anatomical pathology of Brazilian anteaters. Considering the relevance of knowledge of diseases of these species for their conservation, the aim of this study was to describe pathological changes in 99 captive and free-ranging anteaters from the Brazilian states of São Paulo, Minas Gerais, Bahia, Mato Grosso do Sul and Amazonas. Forty-two animals were killed on roads and 10 died from burns injuries. Other significant conditions included the metabolic diseases of iron storage disease, tissue mineralization and taurine deficiency, protozoan and metazoan infections, candidiasis, sporotrichosis, clostridiosis and proliferative disorders including squamous cell carcinoma.

Automated red blood cell depletion: Results from a validation trial of the Fenwal Amicus new red blood cell depletion program.

A new software release of the Fenwal Amicus device is now available for red blood cell (RBC) apheresis, offering RBC exchange, RBC depletion (RBCd)/RCB exchange, and RBCd procedures. The main goal of this study was to validate the new RBCd program through the accuracy of the patient's postprocedure hematocrit (HCT) (actual end HCT) to the HCT reported by the device at the end of the procedure (target end HCT). Secondary objectives were to assess the device-related significant adverse events, the patient's cellular losses, and the degree of device induced hemolysis. The study was an open-label, single-center, prospective trial in adult patients eligible for RBCd. Patients were enrolled between October 2015 and June 2016. In all procedures, saline was used as replacement fluid. Blood samples were collected from the patient before and after the procedure. Device settings, adverse events, and procedure results were recorded. Thirty-nine patients were enrolled (34 treated for iron storage disease and 5 for polycythemia vera); only 36 were evaluable for the primary objective. The mean actual end HCT was 34.6 ± 2.79% and the mean target end HCT was 35.8 ± 2.25%. The ratio (actual end to target end HCT) was 0.97 ± 0.05 with a 95% CI demonstrating the accuracy of the target HCT. One patient experienced a vasovagal event not related to the device. Cellular losses were not clinically relevant. The RBCd Amicus program met all RBCd efficiency and safety requirements with high accuracy of the target HCT.

Long-term Outcome of Orthotopic Liver Transplantation in Patients With Hemochromatosis: A Summary of a 30-year Transplant Program.

Background.Hemochromatosis (HC) is an autosomal recessive disease characterized by impaired iron metabolism and a rare indication for orthotopic liver transplantation (LT). Data about iron reaccumulation and remodeling of the liver graft after LT are limited. Therefore, we performed an evaluation of the histopathologic changes during long-term follow-up in patients with HC.Methods.A retrospective analysis of patients undergoing LT at our center between 1990 and 2016 identified 29 patients with HC. End points were the evaluation of post-LT iron reaccumulation and the stage of fibrosis as well as the degree of inflammation of the liver graft. Secondary end points were patient survival and postoperative complications.Results.The median age was 52.7 y, and there were more male (82.8%) than female patients (17.2%). Post-LT serum ferritin values (>1000 μg/L) were only temporarily elevated in 2 patients. The median estimated survival after LT was 45.5 mo (0.1–285.9 mo). Twenty patients (69%) died during follow-up of 10 y. The survival of patients with HC was significantly worse (P = 0.001) when compared with the overall cohort of patients undergoing LT because of to other causes.Conclusions.There was no significant iron overload detected in patients with HC after LT, and only minimal iron deposits were described in liver biopsies. Nevertheless, patients suffering from HC show a lower post-LT survival when compared with patients without iron storage disease but mostly because of extrahepatic causes.

Identification of heterozygous p.Y150C and p.V274M mutations in the HJV gene in a Japanese patient with a mild phenotype of juvenile hemochromatosis: A case report.

Juvenile hemochromatosis (JH) is known as a progressive iron-storage disease, and causes severe organ impairments, including cardiomyopathy and liver cirrhosis. However, JH is a rare genetic disorder, and information for genetic mutations and phenotypes is limited. Here, we report a case of JH with heterozygous p.Y150C and p.V274M mutations in the HJV gene. A 39-year-old Japanese man was referred to Kurume University Hospital, Kurume, Japan, for fatigue and liver injury, which first appeared at the age of 25years. There was no history of alcohol abuse and medication, and viral hepatitis, autoimmune liver diseases, and Wilson's disease were absent. However, transferrin saturation, serum ferritin, and fasting serum hepcidin levels were 98.4%, 6421ng/mL, and 7.4ng/mL, respectively. Furthermore, a marked reduction in signal intensity of the liver in T1/T2-weighted magnetic resonance images was seen and the R2* maps showed hepatic iron overload. Family history of hemochromatosis and severe organ impairment, such as cardiac dysfunction and diabetes mellitus, were negative. In addition, the HFE and HAMP genes did not show any mutation. However, we identified novel heterozygous p.Y150C and p.V274M mutations in the HJV gene in the patient. The p.Y150C and p.V274M mutations were seen in his mother and father, respectively. After phlebotomy, fatigue disappeared and serum transaminase levels were normalized. Furthermore, R2* maps showed a reduction of hepatic iron concentration. We first demonstrated heterozygous p.Y150C and p.V274M mutations in the HJV gene of patients with a mild JH phenotype. Thus, genetic testing should be considered even in patients with a mild phenotype of hemochromatosis.

Can iron storage disease be induced by a chronic infection such as tuberculosis in Asian elephants (Elephas maximus)?

Can iron storage disease be induced by a chronic infection such as tuberculosis in Asian elephants (Elephas maximus)?

Eryptosis in Haemochromatosis: Implications for rheology.

Haemochromatosis is an iron-storage disease with different genetic mutations, characterized by an increased intestinal absorption of iron, resulting in a deposition of excessive amounts of iron in parenchymal cells. When the iron is released in the blood, it is left in an unliganded form, where it can participate in Haber-Weiss and Fenton reactions, creating hydroxyl radicals. Erythrocytes (RBCs) are particularly vulnerable to hydroxyl radical damage, which can result in eryptosis (programmed cell death similar to apoptosis). Here, we used flow cytometry to study the presence of eryptosis in the main genotypic variations of HFE (heterozygous and homozygous C282Y; H63D; C282Y/H63D). We also viewed RBCs from the different mutations using super-resolution Airyscan confocal microscopy. Flow cytometry showed significant changes in membrane biochemistry, indicated by the presence of phosphatidylserine (PS) proteins on the outer leaflet of the membrane, as well as increased intracellular calpain. This was found in all of the studied mutations. Airyscan fluorescence revealed PS flip and also microparticles from RBCs. Such microparticles are known to be pro-inflammatory. We conclude that RBC pathology is present in all the studied HFE mutations, even in low penetrance mutations, and this might affect rheology in these individuals.

The composition of captive ruffed lemur (Varecia spp.) diets in UK zoological collections, with reference to the problems of obesity and iron storage disease

The formulation and provision of appropriate captive diets for zoo animals is important in ensuring the continued health of populations. Inappropriate diets can lead to a number of nutritional deficiencies and increase the risk of disease and obesity. Ruffed lemurs are the most intensely frugivorous of extant lemur species. Captive animals, however, are often fed a diet which may not accurately reflect the composition of the wild diet. As such, the species is prone to obesity and can suffer from nutrition-related diseases. Here we describe the historical diets of several captive populations of ruffed lemurs in the UK, describing differences in nutritional content with a particular focus on the problems of obesity and iron storage disease. Dietary data were collected from six zoological institutions. Comparative analyses were conducted to investigate differences in the amount metabolisable energy, carbohydrates, sugar and iron provisioned per individual, between institutions. The results showed that the composition of captive ruffed lemur diets, and the amount of food offered, differed between institutions. All dietary analytes showed significant variation, with metabolisable energy exceeding suggested maintenance energy requirements at all institutions. One population was found to be obese, and two institutions reported mortalities where excessive iron accumulation and iron storage disease was observed. These data represent an important addition to the literature as they describe historical inconsistencies in the diets of captive ruffed lemurs. Given the degree of variation in diet, morphology, physiology, and oro-rectal through-time amongst nonhuman primates, and the evidence of obesity and disease presented herein, the development of species-specific diets is long overdue. Zoos can use our data to inform the development of appropriate contemporary diets, thus improving captive ruffed lemur condition and wellbeing.

Use of Metal-Rich Slag as a Source of Grit and Its Effects on Pigeon Health and Fitness

Uptake, utilization and physiological effects of slag as a source of grit were studied in laboratory pigeons provided with an ad libitum supply of a) industrial metal-rich slag b) pristine gravel or c) a combination of the above, over a one-year period. Although retention times undoubtedly differed, both grit types appeared to remain within the gizzard until near-completely abraded, thus resulting in near-maximal exposure of the bird to intrinsic metal loads present. Mortalities were confined to the slag-treated group (62%) and birds given choice (11%) with no deaths among gravel-treated controls. Surviving slag-treated birds indicated marked weight increases in both liver (2-fold) and kidney (~ 46%) whereas body fat scores and breast muscle mass were substantially reduced. Slag ingestion likewise affected marked hypertrophy of the parathyroid glands. Tissue metal assays indicated a striking accumulation of Fe (7-8 fold) in liver, and to a lesser extent in bone (3.2-fold) and kidney (1.5-fold) of slag-treated birds. Histologically, hepatocytes and invading clusters of macrophages appeared stuffed with numerous pigmented cytoplasmic granules – histochemically identified as predominantly stored Fe. These findings point to the development of an acute toxic Fe storage condition, not unlike avian hemosiderosis (iron storage disease), as the prime cause of morbidity and eventually death of these slag-treated birds. Long bones of slag-treated birds were substantially more pliable, of reduced strength, and characterized by significantly reduced Ca levels compared to control birds. Histological examination of keel and tibiotarsal bones revealed moderate to severe mineral resorption, with thinning of cortical layers in lamellar bone and reduced cross-strut formation in cancellous bone. Evidence of active woven bone formation at these foci was likewise confirmed, thus corroborating the marked hypertrophy of parathyroids and implied changes in parathyroid function. Given free choice, birds were basically non-selective, rather than exclusive, in their uptake of gravel versus slag. Given that slag was not avoided, and in light of its profound adverse physiological effects, concern for the ecological implications of the vast quantities of exposed slag within our environment and its potential health risks to wild bird populations is warranted.

Iron storage disease (hemochromatosis) and hepcidin response to iron load in two species of pteropodid fruit bats relative to the common vampire bat.

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.

Recovery of black-necked swans, macrophytes and water quality in a Ramsar wetland of southern Chile: Assessing resilience following sudden anthropogenic disturbances

In 2004 migration and mortality for unknown reasons of the herbivorous Black necked swan (Cygnus melancorhyphus (Molina, 1782)) occurred within the Río Cruces wetland (southern Chile), a Ramsar Site and nature sanctuary. Before 2004, this wetland hosted the largest breeding population of this water bird in the Neotropic Realm. The concurrent decrease in the spatial occurrence of the aquatic plant Egeria densa Planch. 1849 - the main food source of swans - was proposed as a cause for swan migration and mortality. Additionally, post-mortem analyses carried out on swans during 2004 showed diminished body weight, high iron loads and histopathological abnormalities in their livers, suggesting iron storage disease. Various hypotheses were postulated to describe those changes; the most plausible related to variations in water quality after a pulp mill located upstream the wetland started to operate in February 2004. Those changes cascaded throughout the stands of E. densa whose remnants had high iron contents in their tissues. Here we present results of a long-term monitoring program of the wetland components, which show that swan population abundance, body weights and histological liver conditions recovered to pre-disturbance levels in 2012. The recovery of E. densa and iron content in plants throughout the wetland, also returned to pre-disturbance levels in the same 8-year time period. These results show the temporal scale over which resilience and natural restoring processes occur in wetland ecosystems of temperate regions such as southern Chile.

Feasibility Study of NMR Based Serum Metabolomic Profiling to Animal Health Monitoring: A Case Study on Iron Storage Disease in Captive Sumatran Rhinoceros (Dicerorhinus sumatrensis).

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.

A RETROSPECTIVE STUDY OF THE LESIONS ASSOCIATED WITH IRON STORAGE DISEASE IN CAPTIVE EGYPTIAN FRUIT BATS (ROUSETTUS AEGYPTIACUS).

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.

Hemochromatosis

Hereditary hemochromatosis is a frequent autosomal recessive iron storage disease in northern and western Europe. The classical clinical triad of liver cirrhosis, hyperpigmentation and diabetes is nowadays rare, most probably because of early recognition. The homozygous C282Y mutation in the HFE gene is responsible for most cases of hereditary hemochromatosis, although other much rarer mutations in other genes have been recently identified. Progressive iron overload not only causes liver cirrhosis but also triggers development of a characteristic arthropathy. Bony swelling with intermittent arthritis of the second and third metacarpophalangeal joints is typical as well as occurrence of chondrocalcinosis in wrists and knee joints. The therapy of choice is excess iron removal by phlebotomy. Treatment usually prevents or even reverses liver damage but does not alter the course of hemochromatosis arthropathy.

Hemochromatozės diagnostika ir autopsijos reikšmė. Klinikinis atvejis

Hemochromatozė – bronzinė liga, kitaip dar vadinama geležies pertekliaus ar geležies kaupimo liga, kuriai būdingas organų (ypač kepenų, taip pat – kasos, širdies, sąnarių, kaulų, hipofizės, odos, nagų) pažeidimas dėl geležies pertekliaus organizme. Paveldima hemochromatozė yra viena dažniausių genetinių ligų tarp baltosios rasės žmonių. Šiaurės Europos populiacijoje nustatoma 1 iš 220-250. Pirminė hemochromatozė – tai autosominiu recesyviniu būdu paveldima liga, dažniausia susijusi su HFE genu. Pirminės hemochromatozės eiga iki vidutinio amžiaus (40-60 metų) asimptominė. Hemochromatozei būdinga triada: kepenų cirozė, cukrinis diabetas ir odos hiperpigmentacija. Kardiomiocitų pažeidimas sukelia širdies veiklos nepakankamumą ir gali būti staigios mirties priežastis. Dažniausiai liga diagnozuojama atsitiktinai – nustačius padidėjusią geležies koncentraciją kraujo serume ir pasireiškus sunkioms, kartais mirtinoms komplikacijoms. Sergant paveldima hemochromatoze nustatomas padidėjęs serumo feritinas bei transferino įsotinimas. Paveldimą hemochromatozę diagnozuoti padeda genetinis ištyrimas – HFE geno C282Y, H63D mutacijų nustatymas. Pagrindinis hemochromatozės gydymo principas – sumažinti geležies toksinį poveikį. Pirminės hemochromatozės gydymo būdas yra flebotomija (kraujo nuleidimas). Pacientams, kuriems flebotomija yra kontraindikuotina arba jie netoleruoja šio gydymo metodo, taikomas medikamentinis gydymas – chelatais, kepenų transplantacija atliekama retai.