Iron
Iron serves as the core of the hæmoglobin molecule and as such is necessary for normal oxygen transport by red blood cells.  Approximately 70% of the body load of iron is found in hæmoglobin, with 10-20% stored, and the remainder found in other complex molecules such as myoglobin and cytochrome.

Dietary iron is absorbed either as complexations in hæm or as elemental iron.  Complexed iron is readily absorbed from the GI tract.  Less dietary elemental iron is absorbed and it must be in the ferrous state for absorption to occur.  Once in the gastric mucosal cell the iron is converted to the ferric state.  Acidic conditions within the stomach enhance elemental iron absorption, which may be increased in times of iron deficiency.

Once absorbed, iron may be stored in the gastric mucosa in the storage form of ferritin or it may be incorporated into transferrin, the transport protein for iron.  Transferrin will deliver dietary iron directly to bone marrow (where it is taken up by a specific receptor) if it is needed for hæmoglobin synthesis or it may deliver the iron to other organs for storage.  In addition to storage as ferritin in the gastric mucosa, iron may be stored as ferritin or hæmosiderin in heart, liver, pancreas, spleen, and marrow.  Ferritin is composed of a water soluble core of ferric hydroxide enclosed in a protein casing (apoferritin).  Hæmosiderin is composed of ferric hydroxide aggregates without the apoferritin shell.  When iron is needed, stores of ferritin are usually utilised first, then hæmosiderin is used.  In addition to increasing dietary iron absorption, other control mechanisms include increased transferrin when body loads of iron are low.  Concurrently, levels of ferritin will decrease in times of iron deficiency.

Iron supplementation is necessary in iron-deficient anæmia.  This usually presents as microcytic (small cell) and hypochromic (pale coloured) red blood cells that are incapable of oxygen transport, due to a deficiency of functional hæmoglobin.  This condition may also occur in premature infants, childhood during rapid growth spurts, pregnancy, lactation, and from severe blood loss.

Parenteral Iron Supplementation -- Iron dextran may be used in patients who cannot absorb iron or in states of severe iron deficiency.  Iron dextran may be administered either intravenously or intramuscularly.
Side effects of IM administration most commonly include pain and tissue staining.  Rapid IV administration may cause headache, lightheadedness, fever, and arthralgia.

Anaphylaxis may rarely occur with either route.  Test doses should be administered to determine if the patient will react adversely to iron dextran.

Oral Forms of Iron Supplementation -- Ferrous sulphate, ferrous fumarate, ferrous gluconate
Oral supplementation of iron is effective in treating this type of anæmia.
Side Effects of oral iron include gastro-intestinal upset and black stools (which may complicate the determination of additional blood loss).  The sulphate salt will produce the greatest incidence of GI side effects.

Acute Toxicity -- Overdose of oral iron may cause necrotising gastro-enteritis, bloody diarrhœa, shock, lethargy, and dyspnœa.  The patient may then appear to improve.  However, they may worsen, presenting with acidosis, coma and death.  NOTE that as little as 10 tablets may be lethal in children.

Treatment of acute toxicity is the iron chelating agent deferoxamine (desferioxamine), which prevents the action and storage of iron and promotes its excretion.
Chronic Toxicity -- Hæmochromatosis, Hæmosiderosis -- generally presents as increased hæmosiderin deposits in heart, liver, and pancreas.  Continued accumulation of the iron may lead to organ failure and death.
Treatment of chronic iron toxicity is usually intermittent phlebotomy.

Cobalamin
The active forms of vitamin B₁₂ are deoxyadenosylcobalamin and methylcobalamin.  These are complex porphyrin ring structures with a central cobalt atom.  Vitamin B₁₂ is also referred to as extrinsic factor (to distinguish it from intrinsic factor, which is an endogenous substance that permits the absorption of vitamin B₁₂).  The ultimate source of cobalamin is microbial synthesis, with the primary dietary sources being meats, eggs, and dairy products.   Cobalamin is stored in large quantities in the liver.  If a deficiency state develops, it may take up to five years for it to become clinically relevant, due to this large store of cobalamin.
Cobalamin is a required co-factor for two different endogenous biochemical reactions.  It is required for the conversion of methylmalonyl CoA to succinyl CoA (via the enzyme methylmalonyl CoA mutase).  Lack of cobalamin with respect to this reaction is thought to be responsible for the neurologic effects of cobalamin deficiency and is likely the result of non-physiologic fat incorporation into the cell membranes of nerves.  The second reaction that requires cobalamin is the conversion of methyltetrahydrofolate to tetrahydrofolate.  This reaction transfers the methyl group to various components in the synthesis of DNA.  Therefore, cobalamin deficiency with respect to this reaction will result in reduced DNA replication.  This is especially noticeable where DNA synthesis is ongoing, such as the production of red blood cells.

Deficiency states of cobalamin most often occur as a result of either a deficiency of intrinsic factor (required for dietary cobalamin absorption) or in cases of malabsorption syndrome (which reduces absorption of dietary cobalamin).  It may also occur with strict vegetarians who do not include eggs or any dairy products in their diet.  NOTE that intrinsic factor deficiency represents a condition termed pernicious anæmia.
Folic Acid (Folate)
The primary dietary sources of folic acid are vegetables, meat, and eggs.  Upon absorption, it is converted to tetrahydrofolate, which is necessary for normal DNA synthesis as described below.

In vivo, folic acid is converted to dihydrofolate and then to tetrahydrofolate by the enzyme folate reductase.  The tetrahydrofolate may then be methylated so that it may serve as a methyl donor in the synthesis of DNA (as described above).  A deficiency of folic acid will result in decreased DNA synthesis.

Folate deficiencies most often occur as a result of inadequate dietary intake.  Patients with a poor diet or who consistently overcook foods (high heat will destroy dietary folate), may present with folate deficiency.

The anæmia associated with folate or cobalamin deficiency is macrocytic (large cell) in nature and is often referred to as megaloblastic anæmia (as noted above the same anæmia caused by a deficiency of intrinsic factor is called pernicious anæmia).  It is characterised by large cells with large nuclei (caused by the accumulation of incompletely form DNA) and increased fragility, which reduces the lifespan of the cell.

Cyanocobalamin, Hydroxycobalamin
Replacement therapy of cobalamin may be accomplished with either cyanocobalamin (oral or parenteral) or hydroxycobalamin (parenteral).  Both agents are converted to the active forms in vivo.  The specific cause of cobalamin deficiency should be determined before initiation of therapy (i.e. if the patient has pernicious anæmia, the oral dosage form would be useless and parenteral administration is required).  Other uses for hydroxycobalamin include cyanide toxicity.  The hydroxycobalamin will bind to CN, preventing its action and hastening its excretion, thus effective as an antidote in CN poisoning.

Folic acid
Replacement therapy is usually through oral supplementation with folic acid.  It is also administered as a supplement during pregnancy to prevent neural tube defects in the fœtus.

Adverse Effects -- There are typically no adverse effects to either cobalamin or folic acid.  Neither compound accumulates in the body to cause toxic effects and both are readily eliminated.

Other Vitamin-Deficiency Anaemias
Pyridoxine (vitamin B6) has also proven helpful in certain sideroblastic anaeamias.  Pyridoxine will be covered later in the course.  Other deficiency-related anaemias (ascorbic acid, copper) are extremely rare.

Mechanism of Action/Pharmacodynamics -- Erythropoietin interacts with a specific receptor in the bone marrow to stimulate red blood cell proliferation and differentiation.

Replacement Therapy -- Epoietin alfa is used to stimulate RBC production in patients with kidney failure (who fail to produce the endogenous hormone) and in patients with zidovudine-mediated anæmia or patients undergoing phlebotomy for surgery or treatment.  Failure to respond to epoietin alfa may require iron and/or folate supplementation.  Epoietin alfa is also abused by some athletes in an attempt to increase the oxygen-transport capability of the blood, thereby reducing anærobic respiration and increasing duration in athletic events.

Adverse Effects -- Increases in RBC may increase the hæmatocrit of the patient, cause hypertension, or lead to the development of thrombi.

Granulocyte colony stimulating factor specifically causes the proliferation and differentiation of granulocytic blood cells.  The human recombinant product is filgrastim.

Granulocyte-Macrophage colony stimulating factor causes the proliferation and differentiation of both granulocytes and macrophages.  The product is sagramostim.

These agents mimic the endogenous myeloid growth factors to increase the production of the respective cells lines.  They are used to increase these blood cells following immunosuppressive chemotherapy and following bone marrow transplant procedures.  In both cases, the incidence of infection is reduced as a consequence of increased white cells and/or macrophages.  They are also used to treat various, specific anæmias.

Adverse Effects

Filgrastim -- may cause bone pain
Sagramostim -- may cause fever, malaise, arthralgia, myalgia, and capillary leaks.