Iron preparation#Iron toxicity and treatment

Iron supplements encourage erythropoiesis to increase red blood cell (RBC) production and oxygen transportation in the circulating system. The transportation of non-heme iron across the apical membrane is through divalent metal transporter 1(DMT1) while that of heme iron is through heme carrier protein 1(HCP1) in the small intestine. Iron is then incorporated and stored as ferritin in macrophages, increasing the iron stock in the body. Ferritin is then converted into an absorbable form of Fe2+ to bind to transferrin - an iron transporter in the blood circulation. The raised in transferrin level carried to the bone marrow cells stimulates RBC production, facilitating oxygen transportation in the bloodstream.

Non-heme and heme oral iron preparations are absorbed into the systemic circulation via different mechanisms.

Non-heme iron is present in a form of Fe3+ and undergoes reduction to Fe2+ in the duodenum by duodenal cytochrome b (Dcyt b). Reduced iron is then imported into divalent metal transporter 1(DMT1) into the enterocyte cytoplasm, either transported into bloodstream by the basolateral transport protein ferroportin or stored as ferritin.

For heme iron, heme oxygenase catalyzes the release of Fe2+ from heme, and Fe2+ enters the enterocyte cytosolic iron pool. However, the uptake mechanism is not well-understood. Haem carrier protein 1(HCP1) has been suggested to transport heme iron into the enterocyte, but has later been proven to have a much higher affinity in the transportation of folate.{{Cite journal|doi = 10.1016/j.febslet.2006.11.048|title = Haem carrier protein 1 (HCP1): Expression and functional studies in cultured cells|year = 2006|last1 = Latunde-Dada|first1 = Gladys O.|last2 = Takeuchi|first2 = Ken|last3 = Simpson|first3 = Robert J.|last4 = McKie|first4 = Andrew T.|journal = FEBS Letters|volume = 580|issue = 30|pages = 6865–6870|pmid = 17156779|s2cid = 34763873|doi-access = free}}{{Cite journal|doi = 10.1016/j.cmet.2006.12.004|title = When is a Heme Transporter Not a Heme Transporter? When It's a Folate Transporter|year = 2007|last1 = Andrews|first1 = Nancy C.|journal = Cell Metabolism|volume = 5|issue = 1|pages = 5–6|pmid = 17189201|doi-access = free}} The absorption of heme iron is 2–3 times faster than non-heme iron.{{Cite journal|pmid = 6764713|year = 1981|last1 = Hallberg|first1 = L.|title = Bioavailability of dietary iron in man|journal = Annual Review of Nutrition|volume = 1|pages = 123–147|doi = 10.1146/annurev.nu.01.070181.001011}}

After absorption, the iron from preparation becomes part of the iron pool in the body. Upon stimulation, the reduction of iron storage Fe3+ in the enterocyte to Fe2+ ferroportin allows the passage of iron through the cell membrane for export. In the blood, ferroportin is then converted to transferrin to reach other tissues.{{Cite journal| issue=Supplement_1 | doi=10.1182/blood-2019-121071| pages=SCI-27-SCI-27 |title=Ferroportin in Erythrocytes: Importance for Iron Homeostasis and its Role in Infection|year=2019|last1=Rouault|first1=Tracey|journal=Blood|volume=134|s2cid=209228716|doi-access=free}}

The gastrointestinal (GI) absorption process depends on many factors, including the dosage form, dose, endogenous erythropoiesis process and diet. The most significant factor regulating iron uptake is the amount of iron present in the body. Iron absorption increases with sufficient iron storage and vice versa. Increased erythrocyte synthesis also stimulates iron absorption in the gut.{{Cite journal|doi = 10.1111/j.1753-4887.1995.tb05480.x|title = Overview and Mechanisms of Iron Regulation|year = 2009|last1 = Bothwell|first1 = Thomas H.|journal = Nutrition Reviews|volume = 53|issue = 9|pages = 237–245|pmid = 8577406}} Therefore, oral bioavailability of iron varies greatly, ranging from less than 1% to greater than 50%.{{Cite journal|title = Human rabies--Texas and New Jersey, 1997|journal = MMWR. Morbidity and Mortality Weekly Report|date = 16 January 1998|volume = 47|issue = 1|pages = 1–5|pmid = 9450721|author1 = Centers for Disease Control Prevention (CDC)}} Uptake of iron can be enhanced by dietary heme iron and vitamin C, while inhibited by calcium, polyphenols, tannins and phytates.

File:Iron sucrose IV drip.jpg

Intravenous iron is administered directly to the bloodstream, in a form of iron carbohydrate complexes, such as iron dextran and iron sucrose. The complex is composed of a polynuclear Fe3+ hydroxide core with a surrounding carbohydrate shell. In the body, the iron complex behaves like a prodrug, releasing the iron from the Fe3+ hydroxide core via metabolism.

After the iron complex reaches the bloodstream, macrophages of the reticuloendothelial system will take up the stable complex by endocytosis. The fusion of endosomes and lysosome provides an acidic and reducing environment for iron complex cleavage. Fe2+ released is then transported by the divalent metal transporter 1(DMT1) to the macrophage cytoplasm and incorporated into ferritin.

Ferritin is temporarily stored in the macrophages as part of the iron pool in the body. Upon stimulation, iron can be transported out as ferroportin and oxidized into transferrin in the sites of action, such as the bone marrow for red blood cell synthesis or in the liver as the storage form of ferritin.

File:Hemoglobin 1hho.gif

Hemoglobin synthesis comprises globin and heme synthesis. The heme molecule is formed by the attachment of an Fe2+ ion to protoporphyrin in the bone marrow cells.{{Cite journal|pmc = 4040894|year = 2014|last1 = Chiabrando|first1 = D.|last2 = Mercurio|first2 = S.|last3 = Tolosano|first3 = E.|title = Heme and erythropoieis: More than a structural role|journal = Haematologica|volume = 99|issue = 6|pages = 973–983|doi = 10.3324/haematol.2013.091991|pmid = 24881043}}

Iron obtained from iron preparation is eliminated from the body in a similar manner as dietary iron. Iron is mostly conserved and recycled in the body with minimal loss.{{Cite journal|doi = 10.3945/ajcn.2009.27439|title = Body iron excretion by healthy men and women|year = 2009|last1 = Hunt|first1 = Janet R.|last2 = Zito|first2 = Carol Ann|last3 = Johnson|first3 = Luann K.|journal = The American Journal of Clinical Nutrition|volume = 89|issue = 6|pages = 1792–1798|pmid = 19386738|doi-access = free}} A very limited loss is estimated to be approximately 1 mg/day,Fairbanks, V. F., et al. (1999) "Modern Nutrition in Health and Disease." Lippincott Williams and Wilkins, Hagerstown. mainly by sweating and epithelial cell exfoliation on the skin, genitourinary tract, and gastrointestinal tract. For women, menstrual bleeding is another route for iron loss.

As a strong catalyst, iron is responsible for conversion of reduced forms of O2 into harmful hydroxyl radicals in the body. Excessive amount of iron leads to production of high dose of reactive oxygen species (ROS). High doses of ROS are cytotoxic and can lead to chronic and acute inflammatory conditions.{{Cite journal|doi=10.1016/0014-5793(92)80911-Y|title=Biologically relevant metal ion-dependent hydroxyl radical generation an update|year=1992|last1=Halliwell|first1=Barry|last2=Gutteridge|first2=John M.C.|journal=FEBS Letters|volume=307|issue=1|pages=108–112|pmid=1322323|s2cid=12303655|doi-access=free}} Therefore, regulation of iron level with iron-binding proteins is essential such as transferrin for the transport and import of iron into cells, and ferritin for iron storage. These iron regulatory proteins prevent the accumulation of toxic cytosolic iron, maintaining a balance between uptake and storage of cellular iron.  

During iron overdose, the protective mechanism is insufficient to limit the cytosolic iron concentration. The massive iron loading fails to match the capacity of ferritin for storage. The high concentration of iron emerges into the bloodstream as toxic non-transferrin-bound plasma iron(NTBI).  In the worst case, high cellular iron concentration accelerates non-transferrin iron uptake, leading to accumulation of NTBI .{{Cite journal|title = Uptake of non-transferrin-bound iron by both reductive and nonreductive processes is modulated by intracellular iron|journal = The Journal of Biological Chemistry|date = 10 June 1994|volume = 269|issue = 23|pages = 16046–16053|last1 = Randell|first1 = E. W.|last2 = Parkes|first2 = J. G.|last3 = Olivieri|first3 = N. F.|last4 = Templeton|first4 = D. M.|doi = 10.1016/S0021-9258(17)33971-6|pmid = 8206903|doi-access = free}}

NTBI is cytotoxic due to its ability to promote the formation of free hydroxyl radicals, one type of ROS {{Cite journal|doi = 10.1042/cs0680463|title = Low-molecular-weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis|year = 1985|last1 = Gutteridge|first1 = J. M. C.|last2 = Rowley|first2 = D. A.|last3 = Griffiths|first3 = E.|last4 = Halliwell|first4 = B.|journal = Clinical Science|volume = 68|issue = 4|pages = 463–467|pmid = 2578915}} Such damage results in swelling and lysis of mitochondria. Iron-loaded cells deplete mitochondrial ATP content and die eventually .

Other than the mechanism of toxicity, four clinical stages of iron toxicity has been classified  

The first stage is the initial stage of excess iron in intestinal system and circulation. High iron concentration causes hemorrhagic necrosis and ulceration of the upper intestine, leading to breakage of intestinal mucosal barrier and blood loss. Moreover, development of NTBI leads to circulatory collapse and reduced consciousness.   

The second stage is relatively stable, with improved consciousness. The decrease in plasma iron level due to cellular uptake creates a false sense of security.

The third stage is the most dangerous phase due to intracellular iron toxicity. Iron catalyzes the mitochondrial inner membrane, resulting in peroxidative damage and upset of oxidative phosphorylation. ATP synthesis is hampered, leading to cellular dysfunction, and even death. Hypotension develops again 2 to 5 days after iron ingestion, in association with severe organ dysfunction involving mainly the liver, heart, and brain. Sudden onset of severe hepatic failure, with hypoglycemia, coagulopathy, and aggravated metabolic acidosis are likely to occur, causing fatal outcome.

The fourth stage is rarely seen as limited cases of iron poisoning can survive the third stage. Patients surviving stage 3 are likely to develop intestinal strictures or obstruction due to scarring.  

Treatment of iron overdose includes gastrointestinal (GI) decontamination, chelation and supportive care. Whole-bowel irrigation can be performed with large amounts of an osmotically balanced polyethylene glycol electrolyte solution to flush out excess iron in the GI tract. In serious cases, iron chelation may be needed by intravenous injection, like deferoxamine. It binds iron and other metal ions with the chelator and is eliminated through the urine. Supportive care may also be necessary for patients with breathing difficulty and GI upset, by offering mechanical ventilation and rehydration respectively .{{Cite journal|title = Management of acute iron overdose|journal = Clinical Pharmacy|date = June 1989|volume = 8|issue = 6|pages = 428–440|last1 = Mann|first1 = K. V.|last2 = Picciotti|first2 = M. A.|last3 = Spevack|first3 = T. A.|last4 = Durbin|first4 = D. R.|pmid = 2663331}}

Ferrous sulfate is widely used for both prophylaxis and treatment of iron-deficiency anemia.“Ferrous Sulfate” Martindale: the Complete Drug Reference, by Sean C. Sweetman, Pharmaceutical Press, 2020.

In 2018, it was the 94th most commonly prescribed drug in the United States, with over eight million prescriptions.[https://clincalc.com/DrugStats/Drugs/FerrousSulfate Ferrous Sulfate - Drug Usage Statistics, ClinCalc DrugStats Database], Sean P.K.. “Ferrous Sulfate.” Ferrous Sulfate - Drug Usage Statistics, ClinCalc DrugStats Database.

File:RECALLED – Ferrous Sulfate Tablets, 325 mg (8390240271).jpg

^* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ferrous gluconate is indicated for both prophylaxis and treatment of iron-deficiency anemia.“Ferrous Gluconate” Martindale: the Complete Drug Reference, by Sean C. Sweetman, Pharmaceutical Press, 2020.

File:Ferrous gluconate.png

^* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ferrous fumarate is used in both prophylaxis and treatment of iron-deficiency anemia.“Ferrous Furmarate” Martindale: the Complete Drug Reference, by Sean C. Sweetman, Pharmaceutical Press, 2020.

^* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

^* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Carbonyl iron is used in both prophylaxis and treatment of iron-deficiency anemia.

Polysaccharide iron complex is used in both prophylaxis and treatment of iron-deficiency anemia.

File:Iron Sucrose Structure.jpg

Iron sucrose is used for patients with iron-deficiency anemia, including those with chronic kidney disease, when oral iron therapy is ineffective or impractical. Iron sucrose is given by slow intravenous injection or intravenous infusion. For haemodialysis patients, it may be given into the venous limb of the dialyser.“Iron Sucrose” Martindale: the Complete Drug Reference, by Sean C. Sweetman, Pharmaceutical Press, 2020.

Iron dextran is given by injection and should be used only in the treatment of proven iron-deficiency anemia where oral therapy is ineffective or impracticable.“Iron Dextran” Martindale: the Complete Drug Reference, by Sean C. Sweetman, Pharmaceutical Press, 2020.

Haem iron polypeptide is available in oral and parenteral dosage form. Oral formulation is used in both prophylaxis and treatment of iron-deficiency anemia.“Haem Derivatives” Martindale: the Complete Drug Reference, by Sean C. Sweetman, Pharmaceutical Press, 2020.

Ferric pyrophosphate is used for hemoglobin mainatence in hemodialysis-dependent chronic kidney disease patients.{{Cite web|last=Medical|first=Rockwell|title=TRIFERIC|url=https://www.rockwellmed.com/our-technology/triferic/|access-date=2021-08-18|website=Rockwell Medical|language=en-US}}

• Iron supplement
• Human iron metabolism
• Iron poisoning

Category:Iron

Category:Health care