Iron toxicosis in newborn pigs primarily occurs from administration of excess amounts of oral or parenteral iron supplements. In the acute form of iron toxicosis, clinical signs include pallor, vomiting, anorexia, respiratory distress, icterus, neurological signs, coma, and death. Histopathological examination and chemical analysis can confirm diagnosis. No definitive treatment exists; however, supplementing the sow’s diet with vitamin E or administering injections of vitamin E during late gestation can help to prevent iron toxicosis in piglets.
Newborn pigs are iron deficient and vulnerable to iron-deficiency anemia, and oral or parenteral supplementation in neonates is common. However, free iron in excess of the body’s capacity to bind and sequester it generates free radicals that initiate cross-linking of DNA, lipid peroxidation, and membrane damage. Insufficient stores of antioxidants such as vitamin E can render affected piglets susceptible to the cytotoxic effects of reactive oxygen species (ROS) generated by iron.
In the peracute, anaphylactoid form of iron toxicosis that occurs hours to minutes after supplementation, damage to the tissues at the injection site causes release of potassium and other inflammatory mediators, resulting in cardiovascular collapse and sudden death. In the acute form that occurs within 24 hours after supplementation, clinical signs develop, including pallor, vomiting, anorexia, respiratory distress, icterus, weakness, ataxia, inability to stand, muscle tremors, coma, and death.
Etiology of Iron Toxicosis in Newborn Pigs
Newborn piglets have low liver iron stores and receive only small amounts of iron in sow’s milk. Neonatal iron-deficiency anemia can occur in nonsupplemented piglets within 2–4 weeks after birth. Oral or parenteral iron supplementation is common practice but can result in peracute or acute toxicosis. IV administration has the greatest potential for toxicity, followed by IM injection and PO administration.
Toxicokinetics of Iron Toxicosis in Newborn Pigs
Absorption of Iron
Iron is absorbed in the small intestine by enterocytes in its ferrous (Fe2+) form and transferred to serum, where it is converted to its ferric (Fe3+) form and bound to transferrin. Dietary iron is poorly absorbed from the GI tract; uptake can be increased in the setting of iron deficiency.
Distribution of Iron
Serum iron is primarily bound to transferrin, with lesser amounts bound to ferritin. Circulating serum iron constitutes a storage pool used for synthesis of hemoglobin, ferritin, cytochromes, and other iron-containing proteins. Of the total iron in the body, approximately two-thirds is bound to hemoglobin, 10% to myoglobin and iron-containing enzymes, and the remainder to the storage proteins ferritin and hemosiderin. Ferritin and hemosiderin are distributed throughout the body, with the highest concentrations found in the liver, spleen, and bone marrow.
Iron Metabolism
Nonviable RBCs are removed from circulation by cells of the reticuloendothelial system in the liver, spleen, and bone marrow, where heme is broken down. Iron is heavily conserved and recycled.
Excretion of Iron
Unless bleeding occurs, the body has a limited ability to excrete iron, such as through bile, feces (although most fecal iron comes from ingested iron that was not absorbed), urine, and GI tract mucosal sloughing.
Mechanism of Action of Iron Toxicosis
The mechanism of action of iron toxicosis is via oxidative stress mediated by free radical formation. Free iron in excess of the body’s capacity to bind and sequester it generates free radicals that initiate biomolecular damage (cross-linking DNA, lipid peroxidation, and membrane damage). Ferrous iron (Fe2+) catalyzes formation of free radicals via the Fenton reaction, in which it is converted to ferric iron (Fe3+).
In fatal cases of toxicosis, it has been speculated that insufficient stores of antioxidants such as vitamin E can render affected piglets susceptible to the cytotoxic effects of increased reactive oxygen species (ROS) generated by iron at the cellular level (1). In the peracute, anaphylactoid form of iron toxicosis recognized in swine, damage to the tissues at and adjacent to the injection site is thought to cause release of potassium and other inflammatory mediators, resulting in cardiovascular collapse and sudden death; however, the exact mechanism is not known (2).
Lethal Dose of Iron
Death has been reported in piglets 12–15 hours after receiving 375 mg/kg of iron dextran IM (3). Because toxicity is related to ROS generation, lethal doses might be lower in animals deficient in vitamin E or selenium.
Epidemiology of Iron Toxicosis in Newborn Pigs
Iron toxicosis in newborn pigs is relatively uncommon after injections of iron supplements, but it has been reported sporadically. It is common practice in commercial swine production to administer 100–200 mg of iron dextran IM in the first 3 days of life to prevent iron-deficiency anemia (4). The potential for accidental overdose would thereby be higher in smaller piglets or if multiple injections were given accidentally.
Iron toxicosis in piglets has been associated with vitamin E deficiency in the sows (4), and piglets born to sows deficient in selenium are also reportedly more susceptible to toxicosis. Morbidity and death can be high in affected litters.
Clinical Findings of Iron Toxicosis in Newborn Pigs
Clinical Characterization of Iron Toxicosis
Iron toxicosis has been reported in a number of forms. In some litters, death occurs quickly, ranging from a peracute, anaphylactoid reaction to acute iron toxicosis 2–6 hours after injection. In other, subacute cases, death can be delayed by 2–4 days.
The peracute,anaphylactoid form is characterized by sudden death minutes to a few hours after iron injection. In some ways, this resembles an anaphylactic reaction in its rapidity of onset, vascular collapse, and death. In such cases, most of the litter can be affected.
In acute cases, in which death occurs 2–24 hours after onset, clinical signs can include pallor, vomiting, anorexia, respiratory distress, icterus, weakness, ataxia, inability to stand, muscle tremors, coma, and death. Swelling at the injection site is common.
In some cases of piglets that survive longer than 24 hours, death occurs as a consequence of liver damage, generalized weakness, and secondary infection.
Clinicopathological Findings in Iron Toxicosis
Clinicopathological findings of the acute form of iron intoxication include hyperkalemia and metabolic acidosis due to lactic acidemia.
Postmortem Findings in Iron Toxicosis
At necropsy, tissues around the injection site appear edematous, with yellowish-brown to black discoloration evident in regional lymph nodes. Icterus of tissues can be widespread, and multifocal petechial to ecchymotic hemorrhages are apparent. Microscopic lesions in acute toxicosis include degeneration and swelling of muscle fibers in multiple skeletal muscles (3). Iron-laden Kupffer cells in liver sinusoids are further supportive evidence of recent iron dextran administration (5), and siderophages (hemosiderin-laden macrophages) are commonly observed within lymph node sinuses.
Diagnosis of Iron Toxicosis in Newborn Pigs
Diagnosis of iron toxicosis is generally made based on history, clinical signs, and selective, directed testing. Hemolysis can result in falsely elevated serum iron concentrations, and thus serum iron concentrations should be evaluated with caution.
Pearls & Pitfalls
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Histopathological examination of multiple skeletal muscles from acute mortalities is important for confirming iron toxicity. Iron can be confirmed within degenerate myofibers in affected piglets by Prussian blue staining (6). Prussian blue staining of liver tissues and detection of markedly elevated hepatic iron concentrations by analytical chemistry provide further diagnostic support (see ).
In photomicrograph (A), Kupffer cells contain abundant yellow-brown pigment (H&E stain). In photomicrograph (B), this pigment is confirmed as ferric iron by Prussian blue staining.
Courtesy of Dr. Eric R. Burrough
Treatment and Prevention of Iron Toxicosis in Newborn Pigs
Antidote for Iron Toxicosis
There is no practical specific treatment for iron poisoning in piglets in a production setting. For pigs in research or nonproduction settings, chelation therapy with deferoxamine mesylate may be considered because this has been effective in variety of species; however, few studies specifically examining chelation therapy as a treatment for iron toxicosis have been done in swine (7).
Prevention of Iron Toxicosis
The most important precipitating factor of iron toxicosis in pigs appears to be low vitamin E reserves in the sow. In such cases, the piglets will be born deficient in vitamin E, the colostrum will not be able to provide adequate amounts of vitamin E to meet the antioxidant needs of the nursing animals, or both. Supplementing the sow’s diet with vitamin E, or administering injections of vitamin E during late gestation, will improve the status of the sow and help to prevent iron toxicosis in the piglets.
Key Points
Iron toxicosis in newborn pigs primarily occurs from excess iron supplementation.
Peracute, acute, and subacute clinical forms of iron toxicosis are recognized in piglets.
Vitamin E supplementation of the sow can help to prevent iron toxicosis in piglets.
For More Information
Hooser SB. Iron. In: Gupta RC. Veterinary Toxicology: Basic and Clinical Principles. 3rd ed. Elsevier; 2018:433-437.
References
Lannek N, Lindberg P, Tollerz G. Lowered resistance to iron in vitamin-E deficient piglets and mice. Nature 1962;195:1006-1007. doi:10.1038/1951006c0
Patterson DSP, Allen WM, Berrett S, Sweasey D, Thurley DC, Done JT. A biochemical study of the pathogenesis of iron-induced myodegeneration of piglets. Zentralbl Veterinarmed A1969;16:199-214. doi:10.1111/j.1439-0442.1969.tb00722.x
Arpi T, Tollerz G. Iron poisoning in piglets: autopsy findings in experimental and spontaneous cases. Acta Vet Scand 1965;6(4):360-373. doi:10.1186/BF03547093
Svoboda M, Drábek J. Iron deficiency in sickling piglets: parenteral and oral iron administration to piglets (a review). Folia Vet. 2005;49(3):165-173. https://www.uvlf.sk/document/folia-veterinaria-volume-49-issue-3.pdf#page=52
Lipinski P, Starzyński RR, Canonne-Hergaux F, et al. Benefits and risks of iron supplementation in anemic neonatal piglets. Am J Pathol. 2010;177(3):1233-1243. doi:10.2353/ajpath.2010.091020.
Patterson DS, Allen WM, Berrett S, Sweasey D, Done JT. The toxicity of parenteral iron preparations in the rabbit and pig with comparison of the clinical and biochemical responses to iron-dextrose in 2 days old and 8 days old piglets. Zentralbl Veterinarmed A. 1971;18(6):453-464. doi:10.1111/j.1439-0442.1971.tb00601.x
Gu Y, Hua Y, Keep RF, Morgenstern LB, Xi G. Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke. 2009;40(6):2241-2243. doi:10.1161/STROKEAHA.108.539536
