Iron Storage Disease In Birds

What is iron storage disease?

Some deposition of iron, in the form of hemosiderin, is normal in the liver, spleen, bone marrow, and reticulocytes. Hemosiderosis occurs when the accumulation of iron in hepatocytes becomes visible in histological evaluation, but there are no associated clinical signs. Hemosiderosis may occur for a variety of reasons, all related to high circulating ferritin levels. As a secondary effect of bacterial or parasitic infection, iron does accumulate in macrophages e.g. Kupffer cells in the liver.

Hemochromatosis, “iron overload”, or “iron storage disease” is the excess accumulation of iron within parenchyma, especially in the liver and eventually in the heart and spleen. Elevated iron stores eventually lead to hepatocyte damage and fibrosis. This may be followed by circulatory problems, coelomic effusion, cardiomyopathy, and arthropathy, as well as endocrine and neurodegenerative disorders (Fig 1). Excess iron can also promote the development of infection or neoplasia.

Hemosiderosis occurs in many captive bird species and is a common finding at necropsy. Hemochromatosis in captive avian species is most often diet related, and iron overload is a frequent finding in several zoo animals—many of them rare and endangered species.

Hemochromatosis is most often reported in:

• Piciformes
  • Ramphastidae
    • Toucans
    • Aracari
    • Toucanettes

• Passeriformes
  • Sturnidae
    • Starlings
    • Mynah birds (Gracula spp.)
  • Paradisidae
    • Birds of paradise
  • Emberizidae
    • Tanagers

• Coraciiformes
  • Hornbill spp. (particularly frugivorous species)

Hemochromatosis has also been reported in owls, waterfowl, flamingos, go-away birds , quetzals Pharomachrus species), and psittacines including: citron-crested cockatoo (Cacatua sulphurea citrinocristata), blue-front Amazon parrot (Amazona aestiva), several macaw species, hawk-headed parrot ( Deroptyus spp.), black lory (Chalcopsitta atra), Duyvenbode’s lories (Chalcopsitta duivenbodei), and the rainbow lory (Trichoglossus haematodus).

Basic iron metabolism

Most work on iron metabolism has been done in rats, dogs, and humans. There has been little work done in birds except for poultry. Birds and mammals share some molecules and pathways, but iron metabolism is extremely complex. There are differences seen among mammals that indicate extreme caution must be used when extrapolating information from mammals to birds.

Iron is an essential trace mineral needed for hemoglobin production. Iron also serves as a component of numerous enzymes. Total body iron is controlled by the iron absorption rate in the proximal small intestine. Absorption normally increases as body stores decrease. Stress also increases iron absorption. Absorption is also affected by a variety of factors including age, health status, the amount and chemical form of ingested iron as well as the proportions of other dietary components. For instance, copper, zinc, cadmium, and manganese compete with iron for tissue absorption. True understanding of the factors controlling iron absorption requires that minerals as a group be evaluated as well as other dietary interactions.

Once absorbed, iron is transported in the blood as transferrin, and stored as two non-heme compounds: hemosiderin and, more commonly, ferritin. Ferritin and hemosiderin are found through out the body but particularly in the liver and spleen. As total iron stores increase, the ratio of hemosiderin to ferritin increases.

Pathogenesis

The pathogenesis of iron storage disease (ISD) in birds is poorly understood, but hypothesized causes relate to genetics and diet.

Consider the source and availability of dietary iron. Hemoglobin-based iron, found in meat products such as dog or cat food and pinky mice, is more readily absorbed than non-heme iron. Iron toxicity has also occurred secondary to the use of cast iron bowls with poorly applied enamel.

But why doesn’t ISD usually occur in non-susceptible species fed high dietary iron? And why are susceptible species unable to adequately down-regulate the uptake of iron to prevent iron overload? In humans, hemochromatosis has been linked to a chromosomal defect, which causes decreased loss of iron from cells or increased duodenal iron absorption and enhanced macrophagic iron recycling. A genetic predisposition is also suggested in sensitive avian species. For instance, mynahs and European starlings (Sturnus vulgaris) are more efficient at absorbing dietary iron, and they cannot adequately down-regulate iron absorption when body stores are adequate. Similarities between the histologic distribution of hepatic iron in mynahs with primary hemochromatosis in humans also suggests mynahs and possibly other susceptible species may be genetically predisposed to ISD.

Birds susceptible to ISD may be native to environments where dietary iron levels are naturally low. A survey of foods eaten by free-ranging keel-billed toucans (Ramphastos sulfuratus) found their food items were generally low in iron. Frugivorous species may be at increased risk for ISD because fruits contain low levels of iron. The addition of ascorbic acid to chicken diets increases total body iron, but only when birds are fed a low-iron diet containing 40 ppm as opposed to moderate-iron diets containing 100 ppm.

Clinical picture

The signs of ISD are associated with declining hepatic function and include depression, weight loss, and coelomic distension secondary to hepatomegaly and/or coelomic effusion. Air sac compression may lead to dyspnea. Some authors have also reported vestibular signs, feather picking, and evidence of reproductive failure in birds with ISD, which all could be secondary problems related to liver dysfunction and edema.

Iron accumulates in the cytoplasm of hepatocytes and epithelioid macrophages and may lead to liver pathology. Myocardial necrosis is a rare finding in ISD that may ultimately result in heart failure.

Diagnostics

Antemortem diagnosis of ISD is challenging. Of course the first step is to suspect hemochromatosis, particularly in patients with unexplained liver dysfunction or circulatory problems.

Blood tests

Hematology and serum biochemistry are generally not helpful tests for the diagnosis of ISD, although liver enzymes may be elevated. Serum bile acids levels may be within normal limits, even with severe ISD.

In human patients, batteries of tests are performed including serum iron, serum ferritin, transferrin concentration, examination of ferritin receptors, and transferrin saturation (TS).

• Transferrin levels have been used in birds to diagnose iron overload.
• Serum ferritin levels are not yet available in birds, but we do know that ferritin levels may be elevated for several reasons other than iron overload such as inflammation, infection, hepatic disease, and hemolysis.
• Many human patients have high TS levels exceeding 45-50%. Birds typically have higher TS levels when compared to mammals.
• Serum iron levels and total iron binding capacity are both considered poor indicators of total body or hepatic iron status in birds. Serum iron levels have been reported in psittacines, but the degree of variation was too broad (0.4-11.94 ppm) and a reference range could not be established. More recently, iron reference ranges of 2.25-6.25 ppm have been reported in Hispaniolan Amazon parrots (Amazona ventralis). The authors proposed that values exceeding 6.25 ppm may suggest hemochromatosis although values within the reported range do not rule out disease.

 

Table 1.

Mean total iron binding capacity (TIBC), unbound iron-binding capacity (UIBC), and transferring saturation (TS%) in control white leghorn chickens and domestic pigeons for 30 days. Data expressed as means + SD (Whiteside 2004).

	White Leghorn Chickens	Domestic Pigeon
TIBC (µmol/L)	71.90 + 11.54	48.35 + 10.62
UIBC (µmol/L)	2.65 + 5.08	4.33 + 4.59
TS%	95.40 + 8.73	85.3 + 15.19

Imaging

Common radiographic changes in birds with ISD include hepatomegaly, cardiomegaly and ultimately coelomic effusion. Although there are inherent technical challenges involved in ultrasounding birds, this technique can be useful in guiding biopsy or identifying gross structural changes in the liver.

Magnetic resonance imaging (MRI) is often used to screen for iron overload in humans. Although MRI is not definitively diagnostic for iron accumulation, other liver diseases that reduce signal intensity in humans cause nodular regions instead of the diffuse decrease in signal intensity seen with hemosiderosis. Multiple human studies also show a correlation between hepatic MRI tissue signal intensity and the quantity of iron present.

Liver biopsy

Definitive diagnosis of ISD relies on histology or toxicology of liver tissue. Non- heme liver iron levels in starlings dying of ISD ranged from 4000-8000 ppm. While normal reference ranges for hepatic iron levels are not available for most avian species, that level should generally be lower than 500 ppm. Liver iron levels are influenced by age, and seasonal events such as migration or molting. Iron mobilization also varies in female chickens during different phases of the reproductive cycle.

Although there are inherent anesthetic and surgical risks involved, liver biopsy is currently the most reliable and direct method to evaluate iron status antemortem. Histology of clinical cases with ISD will reveal distorted hepatic structure with numerous, dense nodules of macrophages and swollen cytoplasm (Fig 2). Hepatocytes and macrophages are heavily loaded with brown pigment that stains positive with the iron-specific stain, Prussian blue (Fig 3).

Pathologists assess prognosis by subjectively grading fibrosis and looking for associated lesions. Quantitative computerized image analysis of liver biopsy samples has also been used to objectively assess changes in hepatocellular iron levels. In fact, it has been proposed that histologic evaluation without image enhancement may be too insensitive to detect small but significant increases in liver iron stores in non-clinical cases.

Monitoring iron status

The most accurate way to monitor iron status in birds is through liver biopsies. Hepatic MRI may also be used after a definitive diagnosis has been made by biopsy to monitor changes in signal intensity associated with hepatic iron stores.

Treatment

Therapy generally includes phlebotomy, iron chelation, and/or manipulation of dietary iron. The treatment of choice will depend on finances, the stress of treatment, and the ability of the bird owner to perform injections. Unfortunately, once a bird is seriously ill due to significant iron deposition and related fibrosis, treatment may be too late.

1. Feed a low-iron formulated diet:  Dietary modification tends to work better as a preventive measure than treatment, however decrease or eliminate meat products such as pinky mice, dog food, or cat food since hemoglobin-based iron is more readily absorbed than non-heme iron. Fortunately these items are rarely a major part of the diet of sensitive birds.Ascorbic acid and other organic acids may enhance iron absorption when fed with the dietary iron source. Although the role of vitamin C in ISD has been debated, it is prudent to strive for no more than 100 mg vitamin C/kg dry matter basis and to feed vitamin C-rich dietary items separately from iron-rich items.Even if meat and fruits are eliminated from the diet, the current recommendation is to feed susceptible species a formulated diet with less than 100 ppm of iron supplemented with non-citrus fruit. Unfortunately, commercial production of a balanced diet containing less than 100-125 ppm of iron is exceedingly difficult.  Editor’s note: Studies have shown, ascorbic acid does not enhance iron absorption.
2. Phlebotomy:  Phlebotomy is the most common treatment in human patients. A blood volume equal to approximately 0.7% of body weight is removed once or twice weekly thereby forcing the body to mobilize iron stores.Monitor hematocrit since phlebotomy can induce iron-deficiency anemia. Phlebotomy is contraindicated in patients with severe heart disease or anemia. If a bird becomes anemic, halt phlebotomy and allow hematocrit to return to normal before continuing treatment.
3. Chelation therapy:  The parenteral iron-chelator, deferoxamine, also known as desferoxamine mesylate (Desferal®, Novartis) (DFO), is used in human patients when phlebotomy is not possible. Potential complications that have been observed in humans include rare ocular, auditory, and neurologic signs, abnormal cartilage formation or stunted growth in young patients, hypersensitivity reactions and injection site reactions, as well as pancytopenia and increased risk of rare bacterial or fungal infection. The frequency of most of these adverse reactions has not been established.Variable clinical results have been reported with DFO use in birds. There are reports of success with DFO 100 mg/kg SC q24h in starlings, and there are confirmed reports of marked reduction in hepatic iron in 2 channel-billed toucans (Ramphastos vitellinus). Deferiprone (Ferripox®, ApoPharma) is an oral iron chelator licensed for use in Europe and Asia. Deferiprone is currently in Phase IV clinical trials for patients with thalassemia by the United States. A single dose (50 mg/kg PO or IV) in chickens promoted a rate of decrease in total liver iron that was 3-20 times faster than in birds treated with DFO. Based on half-life, Whiteside recommended a twice-daily dosage for 30 days, and this dose regimen has been recommended clinically in toucans. Up to 39% of human patients on deferiprone develop joint lesions, but this problem was not observed in chickens or pigeons. Unfortunately 3 chickens in Whiteside’s study died and the cause of death could not be determined. Deferiprone has a strong affinity for iron but it also binds zinc, copper, and aluminum. Therefore this chelator is not recommended for prophylaxis because of the risk of zinc deficiency.Both phlebotomy and injections can be stressful for birds and it can be difficult to know which procedure to choose or if combination therapy should be started. Phlebotomy or deferoxamine in combination with a low-iron diet containing 23 ppm reduced non-heme liver iron levels in starlings by 163-190 ppm per week. Treatment for at least 16 weeks was recommended.
4. Natural chelators:  The addition of natural chelators to the diet is a common suggestion for birds with ISD, but this can be difficult to implement. The phytate, inositol hexaphosphate, is found in bran and other plants and may markedly inhibit dietary iron absorption. Polyphenols are a group of chemicals found in plants that share a core phenol group. Tannins are a type of polyphenol used by plants to defend themselves against herbivores. Tannins strongly bind iron, and it has been theorized that wild birds may drink rainwater that has been filtered by tannins from tree cavities. Plant sources of tannins include: tea leaves (green or black), fruits such as cranberries, blueberries, purple and red grapes, tree or shrub leaves including willow (Salix spp.), sumac (Rhus spp.) various maples (Acer spp.), and forages such as Lespedeza.Tannins are complex compounds that must be used with caution. Tannins bind with other minerals, proteins, starches, and cellulose, and they can potentially reduce protein digestion and cause anorexia. For this reason, tannins should probably be used for treatment of ISD and not prevention. Of course tannins will only limit additional increases in liver iron stores.There has been some experimental work with natural chelators in birds. Wild-caught starlings were given supplemental black tea leaves by soaking their food in brewed tea every other month. Despite being on an iron-enriched diet, hepatic iron levels did not increase. In a separate study, the addition of inositol (20 g/kg wet weight) and tannic acid (20 g/kg wet weight) to a high-iron diet prevented excess iron uptake in starlings.

 

Conclusion

It appears that both genetics and diet contribute to the development of hemosiderosis and ISD. However iron overload in birds is extremely complicated and this topic calls for further study.

Iron content of select Lafeber bird foods

Appendix I. Iron content of select Lafeber Company pet bird foods
Pet Bird Food	Iron content (mg/kg as fed)*
Classic Nutri-Berries Macaw	111
Classic Nutri-Berries Parrot	165
Classic Nutri-Berries Cockatiel	108
Classic Nutri-Berries Parakeet	99
Premium Daily Diet Pellets Macaw	184
Premium Daily Diet Pellets Parrot	170
Premium Daily Diet Pellets Cockatiel	207
Premium Daily Diet Pellets Parakeet	200
*Where 1 ppm = 1 mg/kg

References