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Home , Iron poisoning

Brief managing common in companion animals

PEER-REVIEWED The of , an essential element Jay Albretsen, DVM, PhD, DABT, DABVT TABLE 1 Iron Salts and ron is the most abundant trace min- salts are but is about a fourth as toxic.1,2,4 the Percentage eral in the body and is an essential Product labels do not always indicate if of Elemental Iron* element in most biological sys- the iron is chelated. Most products that I 1,2 tems. It is likely that iron was essential Elemental contain iron have it in a salt form. Table for developing aerobic life on Earth.3 Form of Iron Iron (%) 1 lists several iron salts and the percent- But iron is toxic to cells in excessive Ferric hydroxide 63 age of elemental iron in each. amounts. Acute iron is com- Ferrous carbonate (anhydrous) 48 mon and potentially lethal in dogs, cats, Ferric phosphate 37 Iron absorption and many other animals. Iron is also a Ferrous sulfate (anhydrous) 37 leading cause of unintentional poisoning Ferric chloride 34 Iron absorption is a two-step process. deaths in children less than 6 years old. Ferrous fumarate 33 First, iron ions are absorbed from the Ferric pyrophosphate 30 intestinal lumen into mucosal cells. Fer- rous iron is better absorbed than ferric Normal iron content and storage Ferrous lactate 24 Ferrous sulfate (hydrate) 20 iron because ferric iron precipitates out About 70% of the iron in mammals is Peptonized iron 17 of solution at around pH 7 or under found in , and about 5% to Ferroglycine sulfate 16 normal physiologic conditions.7 How- 10% is found in myoglobin. When Ferric ammonium citrate 15 ever, both forms can be absorbed if bound to normal hemoglobin and Ferrous gluconate 12 they are ionized.1,2,5 Because iron must myoglobin, iron is in the ferrous (Fe2+) Ferrocholinate 12 be ionized to be absorbed, metallic iron 1,2,4 form. Up to 25% of iron in the body *Source: References 1-3. and iron oxide (rust) are not generally is in the ferric (Fe3+) form and is stored of concern when they are ingested.1,2 in hemosiderin, , and available. Many are brightly colored and Most iron absorption occurs in the duo- in the , spleen, and bone mar- sugarcoated, making them attractive to denum and upper jejunum, but in ani- row.1,2,5 Ferric iron is used in iron- animals and small children. In addition, mals with iron toxicosis, the iron seems containing enzymes, such as peroxi- several iron supplements are available to be well-absorbed along all parts of dase, catalase, and cytochrome-c. over the counter. Another frequent the intestinal tract.1,2,5,6 A diet high in source of iron overdose in pets is prena- sugar and vitamin C increases iron ab- tal vitamins. Many prescription prenatal sorption, while a high-phosphate diet Sources vitamins contain more than 60 mg of ele- reduces iron absorption.1,2,4,5 But in One reason iron toxicosis is such an mental iron in each pill, so animals can acute overdoses, the iron seems to be important problem is that the general develop severe iron toxicosis even if absorbed in a passive, concentration- public is often unaware of the potential only a few tablets are ingested. dependent fashion, similar to how most toxicity of products that are considered Numerous other products contain other are absorbed. natural and necessary for our health.6 iron, including one-time-use heating Second, iron is transferred to ferritin Another reason is that many phar- pads. Iron can also be found in fertilizers or into circulation bound to transferrin 1,2,4 maceutical preparations contain iron. and pesticides and in the soil. proteins. Transferrin is an alpha1- containing iron are readily Iron is also used in injectable prod- globulin produced in the liver.1,2,7 Com- ucts and is bound to proteins in supple- plexed with transferrin, iron is distrib- “Toxicology Brief” was contributed by Jay ments (chelated iron) to treat iron defi- uted to other iron storage locations in Albretsen, DVM, PhD, DABT, DABVT, Covance ciencies in animals. There are several the body. A unique feature of iron me- Laboratories, 3301 Kinsman Blvd., forms of injectable iron (iron dextran, tabolism is the almost complete absence Madison, WI 53704. The department iron dextrin, iron sorbitol, ferric ammo- of iron excretion. Any iron lost from he- editor is Petra A. Volmer, DVM, MS, DABVT, nium citrate) and several chelated forms moglobin degradation is rapidly bound DABT, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802. of iron. Chelated iron is almost as effec- to transferrin and transported to the tive in treating iron deficiencies as other bone marrow for the resynthesis of he-

82 FEBRUARY 2006 Veterinary Medicine Toxicology Brief continued

moglobin.2,7 Consequently, little iron is First, lactic acidosis occurs because of lost in the urine and feces. In addition, hypovolemia and . Iron iron loss is not notably increased even disrupts oxidative phosphorylation by after iron overdoses.2,4 Most iron loss is interfering in the electron transport through the exfoliation of gastrointesti- chain. Thus, anaerobic metabolism is nal mucosal cells in all mammals and promoted. As ferrous iron is converted through menstrual blood loss.5 While to ferric iron, hydrogen ions are re- anywhere from 2% to 15% of the iron leased, adding to the metabolic acido- ingested is absorbed, only about 0.01% sis. Free iron ions also inhibit the Krebs of the iron body burden is eliminated cycle, and organic acids accumulate.5 every day.1,5 The liver accumulates free iron in Kupffer cells and the hepatocytes. The iron localizes in mitochondria of these Mechanism of action cells and damages several cell orga- When the absorbed iron is not bound nelles.5 Eventually, hypoglycemia, hy- to protein, it produces a variety of perammonemia, coagulation defects, harmful free radicals. Consequently, and hepatic encephalopathy occur.2,5 the concentration of iron is rigorously Free iron inhibits the thrombin-induced controlled in mammalian cells and conversion of fibrinogen to fibrin. His- biological fluids. Acute iron toxicosis topathologic evidence of iron-induced causes both a direct corrosive effect hepatic damage includes cloudy and on the gastrointestinal tract and cellu- swollen hepatocytes, portal iron depo- lar damage due to circulating un- sition, fatty metamorphosis, and mas- bound iron.2 Large doses of iron may sive periportal necrosis.2,4,5 overcome the rate-limiting absorption step and allow excessive iron to enter Toxicity the body. When iron-binding proteins become saturated, free iron ions are Since no mechanism exists for excret- allowed into the general circulation.2,4-6 ing iron, toxicity depends on the Free iron penetrates the cells of the amount of iron already in the body. liver, heart, and . At the cellular Consequently, some animals develop level, free iron increases lipid peroxi- clinical signs of toxicosis even when dation with resulting membrane dam- they receive doses that cause no prob- age to mitochondria, microsomes, and lems in other animals. Iron is most toxic other cellular organelles.1 when given intravenously. Intramuscu- Iron exerts its most profound ef- lar injections are less toxic, and iron fects on the cardiovascular system. Ex- given orally is the least toxic, probably cessive iron can cause fatty necrosis of because the amount of iron absorbed the myocardium, postarteriolar dilata- orally is not 100% of the dose ingested.4 tion, increased capillary permeability, When assessing the potential toxicity of and reduced cardiac output.2 Free iron an iron overdose, the amount of ele- stimulates serotonin and histamine re- mental iron in the products ingested lease as well as systemic metabolic must be determined (Table 1).4 For ex- acidosis caused by lactic acid accumu- ample, if a 500-mg tablet of ferrous glu- lation. All these mechanisms lead to conate was ingested, only 60 mg of ele- shock. Excessive iron also interferes mental iron would have been ingested with clotting mechanisms, augmenting (500 mg 0.12). hemorrhagic processes.1,2,4 Excessive No clinical signs of toxicosis are ex- iron also has been reported to cause pected in dogs ingesting less than 20 thrombocytopenia.5 mg/kg of elemental iron. Dogs ingest- Excessive iron causes metabolic aci- ing between 20 and 60 mg/kg of ele- dosis through several mechanisms. mental iron can develop mild clinical

84 FEBRUARY 2006 Veterinary Medicine Toxicology Brief continued

signs. When the amount of elemental factor synthesis.5 In people, the pres- iron dose is unknown or the animal is iron ingested is greater than 60 mg/kg, ence of hyperglycemia and leukocytosis symptomatic. An abdominal radio- serious clinical signs can develop.2 In often indicates a serum iron concentra- graphic examination can be useful to all animals, oral doses between 100 and tion of greater than 30 µg/dl.2 Finally, identify metallic objects since iron 200 mg/kg are potentially lethal.2,4 iron toxicosis results in several central tablets are radiopaque.2,5 signs. Often these signs result from effects on other cellular Clinical signs Treatment processes. For example, metabolic aci- Iron toxicosis manifests clinically in dosis and can lead to A protocol for treating iron toxicosis is four stages. The first stage occurs in the other signs such as lethargy and hepatic described in Figure 1. Animals that six hours after an iron overdose. It is encephalopathy.5 Other central nervous have recently ingested large doses of marked primarily by gastrointestinal ef- system signs that occur are , iron will benefit from gastrointestinal fects, such as , , and , and tremors.1,2,5 decontamination. In animals that can gastrointestinal bleeding.2,4-6 The great- vomit, induce emesis with 3% hydro- est mucosal damage occurs on an gen peroxide (1 to 5 ml/kg orally), Diagnosis empty stomach. Most animals with apomorphine hydrochloride (0.03 mild to moderate iron toxicosis do not Testing an animal’s serum iron concen- mg/kg intravenously, 0.04 mg/kg intra- progress beyond this stage.5 tration is the best method to confirm muscularly), or other appropriate emet- The second stage occurs six to 24 iron poisoning. It is also beneficial to ics.8 Gastric lavage can be performed hours after the overdose. This is re- measure total iron-binding capacity, al- on anesthetized animals, although it ferred to as a latent period, a period of though neither test alone is sufficient to may not be effective if large pills are apparent clinical recovery. In animals determine whether treatment is needed. involved or if the pills adhere to gastric with severe iron toxicosis, this recovery Most human hospitals offer serum iron mucosa. Place a cuffed endotracheal period is transient and soon progresses concentration and total iron-binding ca- tube to prevent aspiration of lavage to the third stage.2 pacity testing, but not all veterinary clin- material.2 In a recent study, activated The third stage of iron toxicosis oc- ical pathology laboratories do. charcoal adsorbed ferrous sulfate solu- curs about 12 to 96 hours after the initial Since the normal serum iron concen- tion at a pH environment consistent clinical signs develop. This stage is tration and normal total iron-binding ca- with that of the duodenum.9 It has been marked by lethargy, a recurrence of gas- pacity can vary from animal to animal, suggested that iron can be precipitated trointestinal signs, , it is best to measure both and correlate to a nonabsorbable form in the diges- shock, hypotension, tachycardia, cardio- the test results with clinical observa- tive tract by using sodium phosphate, vascular collapse, coagulation deficits, tions. Serum iron concentrations can sodium bicarbonate, or magnesium hy- hepatic necrosis, and possibly death.2,5,6 change dramatically during the first droxide; however, the clinical signifi- The fourth stage, which may occur few hours after ingestion, so repeat the cance of this therapy is questionable.2,4,6 two to six weeks after the iron over- serum iron test four to six hours after Restoring fluids, electrolytes, and dose,2,5 is when animals that had gas- initial measurement. When the serum acid-base balance is essential to suc- trointestinal ulcerations and survived are iron concentration exceeds the total cessfully treating iron toxicosis. Fluids healing. As these ulcerations heal, scar- iron-binding capacity or the serum iron are also needed to prevent hypo- ring occurs and strictures may develop. concentration is greater than 500 µg/dl, volemic shock. Administer fluids based Even animals that had only gastrointesti- severe systemic effects can be ex- on the animal’s maintenance and re- nal irritation in the first stage of iron toxi- pected. Normal serum iron-binding ca- placement needs.2 Monitor electrolytes, cosis are at risk of developing strictures.2 pacity is usually about 25% to 30% sat- and correct any abnormalities. Admin- Other abnormalities noted when iron urated.2 Every laboratory is different, istering gastrointestinal protectants such overdoses occur are dehydration, hypo- but an example of how the serum iron as sucralfate, cimetidine, misoprostol, volemia, , evidence of hepatic concentration and total iron-binding or other inhibitors of gastric acid secre- necrosis (elevated alanine transaminase capacity results are reported is Fe = tion may also be helpful.2,10 and aspartate transaminase activities), 134 µg/dl and total iron-binding capac- therapy is indicated in ani- and liver failure (hypoglycemia, hyper- ity = 436 µg/dl, or 134/436 100 = mals at risk of or showing clinical signs ammonemia).2,5 In addition, iron toxico- 30.7% saturated. of severe iron toxicosis. This includes sis causes coagulation disturbances that Obtaining multiple blood samples animals that ingest more than 60 mg/kg are related to thrombocytopenia, hypo- to test serum iron concentrations may of elemental iron, animals that have a prothrombinemia, and impaired clotting be indicated, especially when the total total iron-binding capacity that is greater

86 FEBRUARY 2006 Veterinary Medicine Toxicology Brief continued FIGURE 1 Management of Iron Toxicosis

The patient has The patient has The patient has ingested < 20 mg/kg ingested 20 to 60 mg/kg ingested > 60 mg/kg elemental iron. elemental iron. elemental iron.

The owner should Decontaminate. Decontaminate. observe the pet at home for at least six hours.

Observe the patient for Administer gastro- at least six hours. intestinal protectants.

No Provide other Are there clinical signs? Yes symptomatic care.

Measure serum iron concentration and total iron-binding capacity.

No further treatment No The serum iron concen- The serum iron concen- Are there clinical signs? Yes or monitoring is needed. tration is < 500 µg/dl. tration is > 500 µg/dl or total iron-binding capacity is greater than Administer supportive Monitor the patient for the serum iron concen- and symptomatic care. at least six hours. tration and the animal is symptomatic. No Is there gastrointestinal No Yes Yes Are there clinical signs? obstruction? Start .

Monitor the patient for Recheck the serum iron four to six weeks. concentration after 24 to 48 hours.

Is the serum iron concentration < 300 µg/dl and are there no clinical signs? Yes No

Continue chelation End chelation therapy. therapy.

88 FEBRUARY 2006 Veterinary Medicine Toxicology Brief continued

than the serum iron concentration, or . If the serum iron con- animals that have a serum iron concen- centration exceeds 500 µg/dl and a tration greater than 500 µg/dl. Deferox- chelator is unavailable, the prognosis amine mesylate (Desferal—Novartis is poor. Pharmaceuticals), the chelator of choice Prevention is the best treatment for for excessive iron in the body, is the iron toxicosis. Teaching owners about only chelator available that seems to be the dangers of iron toxicosis and the effective at reducing serum iron con- importance of keeping all , centrations. The recommended dosage multivitamins, and iron supplements of deferoxamine is 40 mg/kg given in- out of reach of animals will help avoid tramuscularly every four to eight hours. serious injury. Alternatively, give deferoxamine as a continuous infusion at the rate of 15 REFERENCES 1. Goyer RA. Toxic effects of metals. In: mg/kg/hr. Continue chelation therapy Klaassen CD, ed. Casarett & Doull’s toxicology: until the serum iron concentrations de- the basic science of . 5th ed. New York City, NY: McGraw-Hill, 1996;715-716. crease below 300 µg/dl and the clinical 2. Greentree WF, Hall JO. Iron toxicosis. In: signs resolve. Often, iron toxicosis re- Bonagura JD, ed. Kirk’s current therapy XII small animal practice. Philadelphia, Pa: WB quires two or three days of chelation Saunders Co, 1995;240-242. therapy.2,4,5 Deferoxamine causes 3. Williams RJ. Biomineralization: iron and the origins of life. Nature 1990;343:213-214. reddish-colored urine, which indicates 4. Osweiler GD, Carson TL, Buck WB, et al. free iron is being excreted. In people, Iron. In: Clinical and diagnostic veterinary toxi- cology. 3rd ed. Dubuque, Iowa: Kendall/Hunt deferoxamine therapy is continued until Publishing Co, 1985;104-106. the urine color returns to normal.6 De- 5. Hillman RS. Hematopoietic agents: growth factors, minerals, and vitamins. In: Hardman JG, feroxamine has not been reported to Limbird LE, Molinoff PB, et al, eds. Goodman & cause iron deficiency. Gilman’s the pharmacological basis of therapeu- EDTA tics. 9th ed. New York City, NY: McGraw-Hill, Calcium has also been used 1995;1311-1340. to reduce serum iron concentrations 6. Liebelt EL. Iron. In: Haddad LM, Shannon MW, Winchester JF, eds. Clinical management of but has not been shown to reduce poisoning and . 3rd ed. Philadel- mortality in cases of acute iron - phia, Pa: WB Saunders Co, 1998;757-766. 7. Ponka P, Schulman HM, Woodworth RC. ing. An experimental iron chelator, N, Iron transport and storage. Boca Raton, Fla: CRC N’-bis(2-hydroxybenzyl) ethylenedi- Press, 1990. 8. Dorman DC. Emergency treatment of toxi- amine-N, N’-diacetic acid monosodium coses. In: Bongura JD, ed. Kirk’s current veteri- salt (NaHBED), has been used to suc- nary therapy XII small animal practice. Philadel- phia, Pa: WB Saunders Co, 1995;211-217. cessfully treat iron overdoses in dogs 9. Chyka PA, Butler AY, Herman MI. Ferrous and monkeys and was shown to be sulfate adsorption by activated charcoal. Vet Hum Toxicol 2001;43:11-13. about twice as effective as deferoxam- 10. Plumb DC. Veterinary Drug Handbook. 3rd ine and with fewer side effects.11 If ed. Ames: Iowa State University Press, 1999. N HBED 11. Bergeron RJ, Wiegand J, Brittenham, GM. a is approved for use in people, HBED ligand: preclinical studies of a potential it may also become an alternative iron alternative to deferoxamine for treatment of chronic and acute iron poisoning. chelator for animals. Blood 2002;99:3019-3026. ■

Intensive Toxicology Short Course Monitoring and prognosis Common Small Animal Monitor all treated animals for four to Toxicoses six weeks for evidence of gastroin- March 23 and 24, 2006 2 University of Illinois College of testinal obstruction. Once signs of Veterinary Medicine, Urbana, Ill. iron toxicosis have developed, the More than 10 speakers discussing clinical prognosis is guarded. toxicology topics and necropsy procedures, plus an evening reception at Severe iron poisoning requires a lot the ASPCA Animal Poison Control Center of time and effort to treat effectively. For more information, Thus, treatment can become costly. In visit www.cvm.uiuc.edu/ope/satox, addition, it is often difficult to obtain or call (217) 333-2907.

90 FEBRUARY 2006 Veterinary Medicine