Iron Deficiency and Microcytic Anemias

Iron is an essential element for oxygen transport within hemoglobin. Oddly enough it is the element that is missed the most in regards to adequate intake and proper nutrition. Over 1.62 billion people in the world are effected by anemia, which is most commonly caused by iron deficiency. Iron deficiency can be caused by chronic blood loss, and is most common in women and teenagers from loss of blood due to menses. Iron loss leads to increased fatigue and depression, pallor, and dry and splitting hair. It can also lead to confusion cognitive effects. Hemoglobin is made of four polypeptide chains, two of which are alpha, and two are beta that come together to form a tetramer heme group with iron located in the middle. Ferrous iron within each heme molecule reversibly binds to one oxygen molecule. With iron deficiency, there becomes a hemoglobin deficiency. A decreased hemoglobin lowers oxygen-carrying capacity leading to anemia. Anemia by definition is a reduced oxygen-carrying ability. Tissue hypoxia can wreak havoc on almost every cell of the body, and can shift the oxygen dissociation curve in an unfavorable direction. The structure of hemoglobin and its function and key elements can be reviewed here.

To understand iron deficiency its important to recognize important aspects of iron metabolism and transportation in cells. Review the Iron Absorption and Metabolism article here for that information. There are also laboratory values that give a good picture of the iron status within the body that one should pay attention to. Transferrin; which is measured as the total iron binding capacity (TIBC) indicates how much or how little iron is being transported throughout the body. Serum iron is an important indicator of the tissue iron supply, and finally serum ferritin gives a picture of iron storage status within the bone marrow and cells.

Iron Deficiency Anemia

There are three stages within iron deficiency. Each comes with their own classic picture of laboratory results and worsen from stage to stage. In the first stage, there is storage iron depletion. This is mild and the patient may not even feel a difference physically. The patients hemoglobin is normal, normal serum iron, and TIBC. There is however decreased ferritin which indicates that there is decreased storage of iron. The second stage of iron deficiency is characterized by transport iron depletion. The hemoglobin may or may not be abnormal, but there is increased TIBC, and decreased serum iron. An increased TIBC, means that there are more substrate (iron) binding spots within the transferrin molecule. This implies that less iron is binding, which when coupled with a decreased serum iron makes sense. The patient may experience mild anemia which comes with increased fatigue and pallor. A peripheral blood smear will most often start to exhibit anisocytosis and poikilocytosis. These reference indicators represent abnormal sized red cells and abnormal shaped red blood cells respectively. A good indicator is an increased RDW, an increased RDW indicates some degree of anisocytosis. This is accurate because the red blood cell is realizing the loss of this oxygen-carrying capacity so its trying to release red blood cells as fast it can from the bone marrow to compensate for the loss, and as a result these red blood cells will appear smaller in diameter and hypochromic. Hypochromasia indicates that there is less hemoglobin within the cell and there is more of a central pallor. The thought is that even though there is less hemoglobin within each cell, if the bone marrow can produce more of these red blood cells than normal then that equals out. This leads to a microcytic anemia, micro meaning small. Stage three of iron deficiency is often referred to as functional iron deficiency. Within this stage there is an unmistakable decrease in hemoglobin, serum iron, and ferritin. There is also a large increase in TIBC.

The overall effect of iron deficiency anemia on the body and on the bone marrow is ineffective erythropoiesis. The red cell production within the bone marrow is compromised. As a result, the bone marrow becomes hypercellular with red cell precursors reducing the M:E (Myeloid:Erythroid) ratio.

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This picture depicts how a peripheral blood smear would illustrate iron deficiency anemia. The red cells are smaller and there is more of a central pallor to them, indicating a loss of hemoglobin. This is also called hypochromia.

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This picture depicts a normal peripheral blood smear. The red blood cells are larger in size and they have more color to them.

Anemia of Chronic Disease

Anemia of chronic disease is another form of microcytic anemia similar to iron deficiency anemia. It usually arises from a chronic infection or from chronic inflammation, but its also associated with some malignancies. A buildup in inflammatory cytokines alters iron metabolism. IL-6, which is an inflammatory cytokine inhibits erythrocyte production. It also increases hepcidin production. Hepcidin blocks iron release from the macrophages and the hepatocytes by down-regulating ferroportin. Without ferroportin there is no transportation of iron throughout the body and no production of hemoglobin or red blood cells. Laboratory findings will usually demonstrate low serum iron, low TIBC, low transferrin, and an increased to normal ferritin. The reticulocyte count is also normal, and sometimes increased. Reticulocytes are released from the bone marrow in times of red cell shortages to compensate.

This is just a brief overview of iron deficiency anemia and other microcytic anemias. This is just the beginning, follow and look forward to more in-depth reviews of each microcytic anemia. Key differences to look for is the TIBC value. In iron deficiency anemia the TIBC is increased and in anemia of chronic disease the TIBC is decreased. Ferritin is increased in anemia of chronic disease because the stored iron can’t be released from cells and the bone marrow due to the increased hepcidin production. Also the degree of anemia is mild compared to the more severe iron deficiency anemia.

 

 

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Adrenal 101

The adrenal glands also known as the suprarenal glands. Supra meaning above, and renal meaning kidneys. So these glands are situated on top of the kidneys. These are endocrine glands that produce a variety of hormones, but most notable adrenaline, and the steroids aldosterone and cortisol. Each gland has an outer cortex which is divided into three different zones and an inner medulla. The three zones of the cortex are the zone glomerulosa, zone fasciculate, and zone reticularis.

This article will go briefly touch on the structure of the adrenal gland, including each zone of the cortex. Then it will dive into the function of the adrenal gland and the hormones it produces along with their specific cellular target. Finally the article will conclude with an overview of adrenal insufficiency and cortisol overproduction and diseases that illustrate those two conditions.

Structure

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As mentioned earlier, the gland is composed of an outer cortex, and an inner medulla. The outer cortex can be further divided into three zones that each have a specific function.

Zona Fasciculata

The zona fasciculata sits between the other two zones (zona glomerulosa, and zona reticularis) and consists of cells responsible for producing glucocorticoids such as cortisol. Its the largest of the three zones consisting of about 80% of the space in the cortex.

Zona Glomerulosa

The zona glomerulosa is the outermost zone of the adrenal cortex. The cells that are situated in this zone are responsible for the production of mineralocorticoids such as aldosterone. Aldosterone is an important regulator of blood pressure. Review the article covering the Renin-Aldosterone system.

Zona Reticularis

The zona reticular is the innermost cortical layer which is primarily responsible for producing androgens. Its main component synthesized is dehydroepiandrosterone (DHEA), and androstenedione, which is the precursor to testosterone.

Medulla

The medulla is in the centre of each adrenal gland with the cortex around the entire periphery. The chromatin cells within the medulla are the bodies main source of catecholamines. Catecholamines produced in the medulla are adrenaline (epinephrine), and noradrenaline (norepinephrine). Regulation of the synthesis of these catecholamines is driven by the sympathetic nervous system via the preganglionic nerve fibers stemming from the thoracic spinal cord (T5-T11) to the adrenal glands. When the medulla gets stimulated to produce these hormones it secretes them directly into the cardiovascular circulation system, which is unusual of sympathetic innervation as they usually have distinct synapses on specialized cells.

Mineralocorticoids

Mineralocorticoids such as aldosterone are named according to its function. They regulate minerals, such as salt and regulate blood volume (blood pressure). Aldosterone, the most prominent mineralocorticoid acts on the distal convoluted tubules and the collecting ducts by increasing the reabsorption of sodium and the excretion of both potassium and hydrogen ions. The amount of salt present in the body affects the extracellular volume, which influences the blood pressure.

Glucocorticoids

Glucocorticoids are also named due to its function. Cortisol is a prominent glucocorticoid that regulates the metabolism of proteins, fats and sugars (glucose). Cortisol increases the circulating level of glucose. They cause protein catabolism into amino acids and the synthesis of glucose from the amino acids in the liver. They also increase the concentration of fatty acids by increasing lipolysis (fat breakdown) which cells can use as an alternative energy source in situations of glucose absence. Glucocorticoids also play a role in suppression of the immune system. They induce a potent anti-inflammatory effect.

Cortisol

Cortisol is the prominent glucocorticoid produced by the adrenal gland. The adrenal gland secretes a basal level of cortisol depending on the time of day it is. Cortisol concentrations in the blood are highest in the early morning and lowest in the evening as part of the circadian rhythm of adrenalcorticotropic hormone (ACTH) secretion. The article on general endocrinology explains what ACTH is and how it affects the adrenal gland. Basically what happens is the hypothalamus secretes corticotropin releasing hormone that acts on the pituitary to produce ACTH that acts on the adrenal gland cortex to produce cortisol.

Androgens and Catecholamines

The primary androgen produced by the adrenal gland is DHEA, which is converted to more potent androgens such as testosterone, DHT, and estrogen in the gonads. DHEA acts as a precursor. Androgens drive sexual maturation.

Catecholamines are produced by the chromaffin cells from tyrosine. The enzyme tyrosine hydroxyls converts tyrosine to L-DOPA. L-DOPA is then converted to dopamine before it can be turned into norepinephrine. Norepinephrine is then converted to epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT). Epinephrine and norepinephrine act as adrenoreceptors throughout the body, whose primary effect is to increase the blood pressure and cardiac output by way of vasoconstriction. Catecholamines play a huge role in the fight-or-flight response.

Corticosteroid Overproduction

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The normal function of the adrenal gland can be impaired from infections, tumors, autoimmune diseases, or from previous medical therapy such as radiation and chemotherapy. Cushing’s syndrome is the manifestation of glucocorticoid excess. Symptoms and sign are a direct result of chronic exposure to glucocorticoids. Diagnosis is difficult because the symptoms are often nonspecific and pathognomonic of the syndrome in isolation. Symptoms include proximal (distant) muscle weakness, wasting of the extremities, increased fat in the abdomen and face often leading to a moon face, bruising without trauma, and a buffalo hump. A buffalo hump is fat on the back of the neck and supraclavicular pads. In women, menstrual irregularities are common such as oligomenorrhea (infrequent menstrual periods), amenorrhea (absence of menstrual periods), and variable menses. Hyperpigmentation can occur by increased secretion of cortisol. Cortisol acts on the melanocyte-stimulating hormone receptors.

Glucose intolerance is common in Cushing’s syndrome. Primarily due to stimulation of gluconeogenesis by cortisol and insulin resistance caused by the obesity. This leads to hyperglycemia, which can exacerbate any diabetic patient.

Bone loss and osteoporosis is common in patients with Cushing’s syndrome because there is less intestinal calcium absorption. Calcium is vital to bone health and growth. The decrease in bone formation is coupled with an increased rate of bone reabsorption which can lead to more pathological fractures.

Adrenal Insufficiency

Addison’s disease is considered primary hypoadrenalism. There is an inherent deficiency of glucocorticoids and mineralocorticoids. Most commonly caused by an autoimmune condition. Autoimmune means that the body is attacking itself by production of antibodies against cells of the adrenal cortex. In cases of adrenal crisis due to autoimmune primary adrenal insufficiency clinical presentation is usually the patient presenting in a state of shock. Abdominal tenderness upon deep palpation is common. Patients present with hyperpigmentation due to chronic ACTH release by the pituitary. Proopiomelanocortin is overproduced which is a pro hormone that is cleaved into its biologically active hormones corticotropin and melanocyte-stimulating hormone (MSH). This causes increased melanin synthesis, causing the hyperpigmentation. Other non-specific symptoms such as lethargy, fatigue, weakness, confusion, anorexia, nausea, vomiting, or even coma can occur. One of the most commonly presented symptoms is fever and infection, which can be exaggerated by the hypocortisolemia.

Its important to take this article slowly. There a lot of different parts, but the aim was to look at the hormones themselves and how they physiologically act on the body, then take what was learned about those and apply them to two scenarios, hypo/hyperadrenalism and how it affects the body. Cushing’s syndrome is where there is hyperproduction of cortisol primarily leading to many disastrous effects on the body. Addisons disease is an autoimmune disease where the body produces antibodies against the cells of the adrenal cortex, causing destruction of the gland itself, again leading to detrimental effects on the body.

Iron Absorption and Metabolism

Iron is an essential element for almost all forms of life, but most important as an oxygen transporter. When iron is in its ferrous state, oxygen binds to it within the hemoglobin molecule allowing erythrocytes to circulate and deliver oxygen to all the human bodies cells and tissues. The human body also requires iron in order to obtain ATP from cellular respiration (Oxidative phosphorylation). Although iron is an essential element to the body, like anything in nature, too much of it can be toxic. Its ability to donate and accept electrons readily means that it can spontaneously catalyze the conversion of hydrogen peroxide into free radicals. Free radicals cause a wide array of damage to cellular structures and tissues. To minimize the chances of toxicity, almost every iron atom is bound to protein structures, an example being hemoglobin. The iron is bound to the globin protein. To learn more about the structure of hemoglobin, review the previous article written. There is tight regulation of iron metabolism that allows the body to remain in homeostasis. Understanding iron metabolism is important for understanding multiple diseases of iron overload, and iron deficiency.

Iron Absorption

Most of the bodies iron comes from dietary uptake. There is continuous iron recycling occurring within the body from the sequela of hemoglobin metabolism by the spleen. The macrophages of the reticuloendothelial system store iron from the process of breaking down engulfed red blood cells. Its stored as hemosiderin. Hemosiderin is just a defined deposit of protein and iron that occurs as a result of iron overload, either systemically or locally. The metabolic functions of iron depend on the ability to change its valence state from reduced ferrous state (Fe2+) to the oxidized ferric state (Fe3+). Ferrous iron in the lumen of the duodenum is transported across the luminal side of the enterocyte by a protein called divalent metal transporter-1 (DMT1). Once iron has been absorbed across the cell membrane of the enterocyte, it can either be stored by binding to apoferritin or the cell can release the iron through the help of another transporter called ferroportin. Ferroportin is the only know protein that exports iron across cell membranes. One of the ways that the human body manages iron homeostasis is by the production of hepcidin. When iron stores are adequate, the liver will produce hepcidin, which competitively binds to ferroportin and inactivates it. When iron stores begin to drop, suppression of synthesis of hepcidin allows ferroportin to transport iron again. Before iron is taken by ferroportin across the membrane, it must be converted to its ferric form. Hephaestin, another protein on the enterocyte cell membrane oxidizes iron as it exits to its ferric form (Fe3+). Once oxidized and in its ferric state, the iron binds to apotransferrin (ApoTf). This iron:apotransferrin complex is known as transferrin (Tf). Its important to note that two molecules of ferric iron can bind to one molecule of apotransferrin.

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Iron Uptake into Cells

Individual cells regulate the amount of iron they absorb to avoid adverse toxicity. Cells possess a receptor for transferrin (Tf), called transferrin receptor-1 (TfR1). The physiological pH of the plasma and extracellular fluid allow for a strong affinity to transferrin for TfR1. Through receptor mediated endocytosis transferrin saturates the TfR1 and once a critical mass has accumulated, endocytosis begins. The iron is passed into the cell into an endosome vesicle. Hydrogen ions are then pumped into the endosome and as a result the pH drops causing dissociation of the iron from the transferrin. Almost simultaneously the affinity for TfR1 to apotransferrin increases so it remains bound to the receptor while the iron remains free. The iron is then exported from the endosome vesicle into the cytoplasm by divalent metal transporter 1 (DMT1). The molecules of iron are then either stored, or transported into the mitochondria where they are incorporated into cytochromes or heme for the production of hemoglobin. While the iron is transported in the cytoplasm, the endosome fuses again with the cell membrane and in the extracellular space pH, TfR1 has a low affinity for apotransferrin so it dissociates and begins circulating again in the plasma for free transferrin. Again transferrin being a diiron:apotransferrin complex. Cells are able to store iron so they have a reserve if needed. Ferric iron (Fe3+) is stored in a protein called apoferritin. When iron binds to it it known as ferritin. Ferritin can be used at anytime during iron depletion by lysosomal degradation of the protein.

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Regulation

Just like hepcidin, there are other ways that the body maintains iron homeostasis. Transcription of TfR1 on the surface of the cells can either decrease or increase depending on iron stores within the cell. When iron stores are sufficient, production of TFR1 decreases, and vice versa. This is also useful in diagnosis of iron deficiency. Turns out there is a truncated form of TfR1 that circulates in serum as soluble transferrin receptors (sTfR). These sTfRs reflect the amount of tFR1 in the body. So in iron depletion there will be more circulating sTfRs indicating more production of TfR1 on the cells surface. A useful tool in the diagnosis of iron deficiency anemia.

Iron Recycling

When cells die, they are sequestered by the spleen and liver in which mechanisms salvage iron. These mechanisms are often referred to as the haptoglobin-hemopexin-methemalbumin system. Free hemoglobin in the plasma is quickly complexed with haptoglobin. By binding haptoglobin, the hemoglobin, and consequently, the iron avoid filtration by the glomerulus in the kidneys. This complex is taken up by macrophages, primarily those in the liver, spleen, bone marrow and even in the lungs. These macrophages express CD163, which is the haptoglobin scavenger receptor. The entire complex is internalized into the macrophage within a lysosome. Inside this lysosome, the iron is salvaged, the globin is catabolized as any protein would be, and the protoporphyrin is converted to unconjugated bilirubin. To learn more about the process of bilirubin metabolism, review the previous article. The haptoglobin is also degraded by the lysosome. The iron in free hemoglobin becomes oxidized to its ferric state (Fe3+), and as a result, forms methemoglobin. The heme (metheme) molecule of the free hemoglobin binds to hemopexin, preventing oxidative injury to the cells and tissues, as well as prevents loss of iron through glomerulus filtration. Albumin acts as a carrier for many proteins, including metheme. So albumin acts as a carrier for metheme to find hemopexin, which has a much higher affinity for the metheme itself. This allows for more rapid degradation of the toxic metheme.

There was a lot to learn in this article. Read carefully and go back and refer. I will try to highlight certain areas that I think are more important to the bigger picture. The next step is what happens in certain physiological disease states that leads to either iron overload or iron deficiency.

Aspirin as a blood thinner?

Most people who have had previous cardiac issues, those who have even had a minor heart attack or survived a major infarction have often been prescribed to take an aspirin daily. To tackle this issue, its important to understand what a heart attack or an infarction actually is. Usually blood travels to the lungs, it gets oxygenated, and then travels through the coronary arteries to oxygenate the heart muscle itself. People over time can develop plagues that thin the artery lumen, or opening, eventually to the point where only a small amount of oxygenated blood can actually pass through. As a result, the heart can’t keep itself oxygenated. Without oxygen, tissues become hypoxic and die. When they die they release toxic cytokines and chemicals that damage tissue further, which coincidently we can objectively measure to determine whether an individual has experienced a heart attack. Heart attacks can come from a deep vein thrombosis, or an emboli as well. In that scenario, the clot actually happens somewhere else in the body and a piece of it breaks off and circulates until it gets to the heart and blocks the blood flow in the heart, causing an infarct.

Aspirin works as a blood thinner. It impairs the bodies ability to form a clot. What is a clot formed out of? Platelets. So aspirin directly targets a precursor to thromboxane A2, which activates downstream signaling to aggregate platelets and form a clot in primary hemostasis.

Synthesis of TXA2

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The synthesis of thromboxane A2 is through the Arachidonic Acid, Cyclooxygenase (COX) pathway. Phospholipids are converted to Arachidonic Acid catalyzed by phospholipase C or phospholipase A2. Arachidonic acid can at that point go to two pathways; the Lipooxygenase pathway, or the Cyclooxygenase pathway. There are two Cyclooxygenase peroxidase; COX-1 and COX-2. COX-1 mediates the pathway through which thromboxane A2 is going to be synthesized, and COX-2 mediates another pathway that works to synthesize prostaglandins which directly counteract the function of thromboxane A2. Its the bodies way of keeping homeostasis. For every action, there has to be an equal reaction. In the next step in the pathway, Arachidonic Acid is converted to Prostaglandin H2 (PGH2) by PGH2 synthase and COX-1/COX-2 working synergistically. Prostaglandin H2 is then converted to thromboxane A2 (TXA2) by thromboxane synthase. TXA2 is a vasoconstrictor and potent hypertensive agent.

So, how does aspirin come into play at all? Good thing you asked. Aspirin as it turns out irreversibly binds to COX-1. This antagonist effect stops the pathway and does not allow for the synthesis of thromboxane A2. Without TXA2, there will be no platelet aggregation, and no clot. Without primary hemostasis being established, coagulation, or secondary hemostasis, can’t take over to stabilize the clot with fibrin.