Iron supplement

Iron supplements are dietary supplements containing iron that can be prescribed by a doctor for a medical reason, or purchased from a vitamin shop, drug store etc. They are primarily used to treat anemia or other iron deficiencies. There are three ways that it can be delivered: orally, intravenously or intramuscularly.

The first iron pills were commonly known as Blaud's pills,^[1] which were named after P. Blaud of Beaucaire, the French physician who introduced and started the use of these medications as a treatment for patients with anemia.^[2]

Medical uses

Iron supplements are used to treat iron deficiency and iron-deficiency anemia;^[3] parenteral irons can also be used to treat functional iron deficiency, where requirements for iron are greater than the body's ability to supply iron such as in inflammatory states. The main criterion is that other causes of anemia have also been investigated, such as vitamin B₁₂/folate deficiency, drug induced or due to other poisons such as lead, as often the anaemia has more than one underlying cause.

Iron deficiency anemia is classically a microcytic, hypochromic anemia. Generally, in the UK oral preparations are trialled before using parenteral delivery.^[4] unless there is the requirement for a rapid response, previous intolerance to oral iron or likely failure to respond. Intravenous iron may decrease the need for blood transfusions however increases the risk of infections when compared to oral iron.^[5] A 2015 Cochrane Collaboration review found that daily oral supplementation of iron during pregnancy reduces the risk of maternal anaemia and that effects on infant and on other maternal outcomes are not clear.^[6] Another review found that "intermittent regimens (of oral iron supplementation) produced similar maternal and infant outcomes as daily supplementation but were associated with fewer side effects". The quality of evidence was poor, though.^[7]

Athletes

There is debate about whether athletes are at an increased risk for iron deficiencies, and whether athletes with low iron, who are not anemic, would benefit from iron supplementation.^[8]

Despite these additional sources of iron loss, male athletes have normally been observed to receive adequate amounts of dietary iron at the same levels recommended for the average male.^[8] Female athletes, however, have been observed to receive an inadequate supply of iron, but this may be caused more from blood loss from menstruation than from athletic activity.^[8] Additionally, pseudoanemia can be observed in athletes with adequate haemoglobin due to an increase in blood plasma in athletes that dilutes their haemoglobin concentration, making it appear as if they are anemic when they actually have an adequate amount of total haemoglobin.

When an athlete should be recommended to take iron supplements is debated, and should generally be judged on an individual basis.^[8] While iron supplementation can be a pragmatic treatment for athletes that are anemic, its effects remain unclear in athletes that are nonanemic.^[8] Iron supplementation has not been demonstrated to improve athletic performance in individuals who are nonanemic.^[8] For athletes who are nonanemic, however, iron supplementation may function to stave off iron-deficient anemia, as well as prevent excess absorption of toxic metal ions of lead and cadmium.^[8] Due to risks associated with differing individual tolerances, drug interactions, and overdosing, iron supplementation should be directed by a medical professional based off a clinical assessment of the athlete’s iron parameters and not undertaken as self-medication.^[9]

Adverse effects

Side effects of therapy with oral iron are most often diarrhea or constipation and epigastric abdominal discomfort. Taken after a meal, side effects decrease, but there is an increased risk of interaction with other substances. Side effects are dose-dependent, and the dose may be adjusted.

The patient may notice that his/her stools become black. This is completely harmless, but patients must be warned about this to avoid unnecessary concern. When iron supplements are given in a liquid form, teeth may reversibly discolor (this can be avoided through the use of a straw). Intramuscular injection can be painful, and brown discoloration may be noticed.

Treatments with iron(II) sulfate have higher incidence of adverse events than iron(III)-hydroxide polymaltose complex (IPC)^[10][11][12] or iron bis-glycinate chelate.^[13][14]

Contraindications

Contraindications often depend on the substance in question. Documented hypersensitivity to any ingredients and anemias without proper work-up (i.e., documentation of iron deficiency) is true of all preparations. Some can be used in iron deficiency, others require iron deficiency anaemia to be present. Some are also contraindicated in rheumatoid arthritis^[15]

Iron supplementation and infection risk

Because one of the functions of elevated ferritin (an acute phase reaction protein) in acute infections is thought to be to sequester iron from bacteria, it is generally thought that iron supplementation (which circumvents this mechanism) should be avoided in patients who have active bacterial infections. Replacement of iron stores is seldom such an emergency situation that it cannot wait for any such acute infection to be treated.

Some studies have found that iron supplementation can lead to an increase in infectious disease morbidity in areas where bacterial infections are common. For example, children receiving iron-enriched foods have demonstrated an increased rate in diarrhea overall and enteropathogen shedding. Iron deficiency protects against infection by creating an unfavorable environment for bacterial growth. Nevertheless, while iron deficiency might lessen infections by certain pathogenic diseases, it also leads to a reduction in resistance to other strains of viral or bacterial infections, such as Salmonella typhimurium or Entamoeba histolytica. Overall, it is sometimes difficult to decide whether iron supplementation will be beneficial or harmful to an individual in an environment that is prone to many infectious diseases; however this is a different question than the question of supplementation in individuals who are already ill with a bacterial infection.^[16]

Children living in areas prone for malarial infections are also at risk of developing anemia. It was thought that iron supplementation given to such children could increase the risk of malarial infection in them. A Cochrane systematic review published in 2016 found high quality evidence that iron supplementation does not increase the risk of clinical malaria in children.^[17]

Haemochromatosis

Individuals may be genetically predisposed to excessive iron absorption, as is the case with those with HFE hereditary haemochromatosis. Within the general population, 1 out of 400 people has the homozygous form of this genetic trait, and 1 out of every 10 people has its heterozygous form.^[8] Neither individuals with the homozygous or heterozygous form should take iron supplements.^[8]

Interactions

Non-heme iron forms an insoluble complex with several other drugs, resulting in decreased absorption of both iron and the other drug. Examples include tetracycline, penicillamine, methyldopa, levodopa, bisphosphonates and quinolones. The same can occur with elements in food, such as calcium. Absorption of iron is better at a low pH (i.e. an acidic environment), and absorption is decreased if there is a simultaneous intake of antacids.

Many other substances decrease the rate of non-heme iron absorption. Examples are tannins from foods, such as tea and saw palmetto, phytic acid and roughage.^[18] Vegetarians and especially vegans are at increased risk of iron deficiency due to the combination of limited amounts of iron in the diet in a form that is poorly absorbed alongside compounds that further limit absorption.

Taken after a meal, there are fewer side effects but there is also less absorption because of interaction and pH alteration. Generally, an interval of 2–3 hours between the iron intake and that of other drugs seems advisable, but is less convenient for patients and can impact on compliance.

Precautions

Iron overdose has been one of the leading causes of death caused by toxicological agents in children younger than 6 years.^[19]

Mortality/morbidity

Iron poisoning may result in mortality or short-term and long-term morbidity.^[20]

Follow-up

Follow-up is needed to ensure compliance and to detect adequate response to therapy. The interval of follow up can widely depend on both the method of administration, and the underlying pathology. For parenteral irons it is recommended that there be a period of 4 weeks before repeating blood test to allow the body to utilise the iron.^[3] For oral iron, this can take considerably longer, so waiting 3 months may be appropriate.

Administration

Oral

Iron can be supplemented by the oral route using various pharmacological forms, such as iron(II) sulfate (this is the most common and well studied soluble iron salt, e.g. Feratab, Fer-Iron, Slow-FE,…) and in complex with gluconate, dextran, carbonyl iron, and other salts. Ascorbic acid, vitamin C, significantly increases the absorption of none-heme sources of iron.^[21]

Heme iron polypeptide (HIP) (e.g. Proferrin ES and Proferrin Forte) can be used when regular iron supplements such as ferrous sulfate or ferrous fumarate are not tolerated or absorbed. A clinical study demonstrated that HIP increased serum iron levels 23 times greater than ferrous fumarate on a milligram-per-milligram basis.^[22]

Another alternative is ferrous glycine sulfate or ferroglycine sulfate, has less gastrointestinal side-effects than standard preparations such as iron fumarate.^[23] It is unusual among oral preparations of iron supplements in that the iron in this preparation has very high oral bioavailability, especially in the liquid formulation. This option should be evaluated before resorting to parenteral therapy. It is especially useful in iron deficiency anemia associated with autoimmune gastritis and Helicobacter pylori gastritis, where it generally has satisfactory effect.^[24]

Since iron stores in the body are generally depleted, and there is a limit to what the body can process (about 2–6 mg/kg of body mass per day; i.e. for a 100 kg/220 lb man this is equal to a maximum dose of 200–600 mg/per day) without iron poisoning, this is a chronic therapy which may take 3–6 months.^[25]

Due to the frequent intolerance of oral iron and the slow improvement, parenteral iron is recommended in many indications.^[26][27]

Parenteral

Parenteral iron therapy (intravenously or intramuscular) is given when oral therapy has failed (not tolerated by the patient), oral absorption is seriously compromised (by illnesses, or when the patient cannot swallow), benefit from oral therapy cannot be expected, or fast improvement is required (for example, prior to elective surgery).^[28] Parenteral therapy is more expensive than oral iron preparations and is not suitable during the first trimester of pregnancy.

There are cases where parenteral iron is preferable over oral iron. These are cases where oral iron is not tolerated, where the haemoglobin needs to be increased quickly (e.g. post partum, post operatively, post transfusion), where there is an underlying inflammatory condition (e.g. inflammatory bowel disease) or renal patients, the benefits of parenteral iron far outweigh the risks. In many cases, use of intravenous iron has lower risks of adverse events than a blood transfusion and as long as the patient is stable is a better alternative.^[29] Ultimately this always remains a clinical decision based on local guidelines, although National Guidelines are increasingly stipulating IV iron in certain groups of patients.

Soluble iron salts have a significant risk of adverse effects and can cause toxicity due to damage to cellular macromolecules. Delivering iron parenterally has utilised various different molecules to limit this. This has included dextrans, sucrose, carboxymaltose and more recently Isomaltoside 1000.

One formulation of parenteral iron is iron dextran which covers the old high molecular weight (trade name DexFerrum) and the much safer low molecular iron dextrans (tradenames including Cosmofer and Infed.^[30]

Iron sucrose (trade names including Venofer) has an occurrence of allergic reactions of less than 1 in 1000.^[31] A common side effect is taste changes, especially a metallic taste, occurring in between 1 in 10 and 1 in 100 treated patients.^[31] It has a maximum dose of 200 mg on each occasion according to the SPC, but it has been given in doses of 500 mg. Doses can be given up to 3 times a week.

Iron carboxymaltose (trade name Ferinject) is a newer formulation of parenteral iron which is dextran free with the shell being fully metabolised in the body to simple sugars. The most common side effect are headaches which occur in 3.3%.^[32] It can be given over 15 minutes in doses up to 1,000 mg and has been adopted in many hospitals due to the increased number of patients that can be treated as no test dose is required.

Iron Isomaltoside 1000 (Trade name Monofer) is a newer formulation of parenteral iron that has a matrix structure that results in very low levels of free iron and labile iron. It can be given at high doses – 20 mg/kg in a single visit – no upper dose limit. This formulation has the benefit of giving a full iron correction in a single visit.^[33]

Iron carboxymaltose and iron Isomaltoside 1000 both have better safety profiles than older IV preparations, having the ability to be given in larger doses and availing for complete iron replacement in 15–60 minutes.^[34]

See also

• Geritol
• Human iron metabolism
• Iron deficiency
• Iron deficiency anemia
• Lucky iron fish
• Proferrin

References