IRON DEFICIENCY ANEMIA
Iron Deficiency Anemia (IDA) has a pretty self explanatory name lol. But since it’s the most common anemia, you have to know it well.
Cause?
Worldwide, the most common cause is a diet poor in red meat, legumes and certain veggies (spinach). Meat-derived iron exists in the ferrous form (Fe++) and is immediately ready to be absorbed by the belly. Vegetarian-derived heme is less nutritious. It exists in the ferric form (Fe+++) and requires an especially acidic environment to be absorbed. So vegetarians, drink some OJ alongside your spinach to properly absorb it.
In the US, the most common cause is gradual blood loss from menstruation in young women and GI bleeding in the elderly. Occult rectal bleeding is quite common. The patient bleeds a teeny tiny bit from the wall of their gut, and that trace amount of blood becomes practically invisible as it mixes into the brown stool. You can detect occult blood by smearing their feces (yum) onto something called a guaiac card (or the Hemoccult test), and it will change color up in the presence of blood. In an older adult with a new onset IDA, you must rule out colon cancer! Other causes of occult bleeding include peptic ulcer disease, diverticular disease and colon polyps. One other situation to be aware of is pregnancy. Pregnant mothers require extra iron because they’re making blood for two.
How is iron stored and transported around the body?
Iron is one of the ingredients for making Hgb. Here are some (not so) fun facts about this important metal:
Iron is absorbed in the duodenum. The duodenal enterocyte uses a transporter called ferroportin to move Iron into the blood.
Iron is stored in the liver by attaching it to a molecule called ferritin.
Bacteria love Iron. That’s why free iron is barely present in the serum. Instead, the body assigns it an escort, called transferrin. Transferrin transports iron to the bone marrow (to make new RBCs) or to the liver (for storage)
The human body hasn’t evolved a mechanism for getting rid of iron. The treatment for iron overload is routine blood letting!
Pathophysiology of IDA?
You need iron for only one reason -- to make Hgb. Hgb is made by large RBC precursors in the bone marrow called erythroblasts. Each time this cell divides, the erythroblast gets a little smaller. Let’s just say it divides 3 times. It started with 1 cell, and now there are 8 smaller cells. In a patient with IDA, there won’t be much Hgb in each of these 8 cells. The erythroblast notices this, and divides one more time (further shrinking its cytoplasm) to establish a normal concentration of Hgb. That’s why IDA causes microcytosis.
One weird symptom of IDA is pica. Pica is Latin for ‘magpie,’ which is a reference to the magpie's propensity for eating literally anything. Patients with pica crave non-nutritional material (typically clay, ice or paper). There’s no carbs, proteins or fat in dirt. Presumably pica evolved because iron is found in clay. So in a way they really are eating nutritional food!
How do you diagnose IDA?
Order a CBC
↓ Hgb and Hct
MCV < 80 (microcytic) - a normal RBC should be the size of the nucleus of a nearby lymphocyte.
↓ MCH (hypochromic) - less iron → less Hgb → less color. RBCs should have a central pallor ⅓ the size of the cell.
↑ RDW (anisocytosis) - for whatever reason, probably due to daily fluctuations of the body’s iron supply, there will be a wide variety of RBC sizes. On the day before a steak dinner, they might be making puny RBCs, but on the day after, they’ll make big ones. An- (without) -iso- (equal) -cytosis (cells) means that the cells are “without equality” in size.
↓ Reticulocytes - reticulocytes are immature RBCs. The whole problem with IDA is that you can’t make RBCs fast enough, so obviously there won’t be many immature RBCs in the blood because they can’t be created fast enough.
Then order an iron panel.
↓ Iron - there’s low iron everywhere, including free iron in the blood. But serum iron is unreliable.
↓ Ferritin - the body’s bank of iron is depleted. This is a better test for IDA than serum iron because it’s much more stable. Analogy - Serum iron is like the money in your wallet, but the Ferritin is like your money in the bank. If you want to know if someone has a lot of money (iron), then looking into their wallet may be misleading, you would rather look at their bank account.
↑ Total Iron Binding Capacity (TIBC) - this test confused me so much at first. The TIBC is high in IDA, unlike the rest of the iron panel. Here’s how it works. A lab tech takes some of your blood, and puts some iron in it. People with IDA have lots of Transferrin (the transporter) sitting around that isn’t occupied by Iron (because they don’t have iron to begin with). Normally, 1 out of 3 transferrins are occupied. People with IDA can easily handle a little extra iron, hence the HIGH iron binding capacity! It’s always the opposite of ferritin. When the ferritin (iron storage) is low, the body thinks “Oh shit, I need to find more iron! I guess I’ll make some more transferrin, so I can pull some free iron out of the blood!”
Treatment?
Give them an iron supplement or tell them to eat more red meat. If their hemoglobin is less than 8, give a blood transfusion. Then tailor your workup based on the cause. If the cause is menstruation, consider putting them on birth control to lessen their periods. If the patient is elderly, do a colonoscopy to rule out colon cancer.
Plummer Vinson Syndrome - a rare condition with IDA, esophageal webs and dysphagia
Enlarged central pallor
ANEMIA OF CHRONIC DISEASE
Iron sequestration
Anemia of Chronic Disease (AoCD) is a peculiar (but common) occurrence among people with chronic inflammation (longstanding illness, cancer, infection or autoimmune diseases). Inflammation forces the body to hide the iron away, leading to diminished RBC synthesis.
What does inflammation have to do with anemia?
The answer lies with the relationship between iron and bacteria. Bacteria love iron. So the body wants to hide all its iron away. In a state of inflammation, the body assumes that the source of inflammation is an infection. In prehistoric times, this line of reasoning would have been astute. But in the antibiotic era, autoimmunity or cancer are more likely. The body tries to hide all of the iron by moving it out of the blood and into storage (most iron is stored with ferritin in the liver). The liver will contain lots of iron, but the body will have difficulty withdrawing iron from the bank, so to speak. The patient will be left in a state of functional iron deficiency.
How does the body do this?
It makes Hepcidin. Hepcidin is an acute phase reactant (meaning it’s produced by the liver during times of inflammation). Hepcidin facilitates iron sequestration. Fun fact, it also suppresses EPO production by the kidneys, and it blocks iron uptake by the duodenal enterocytes.
Labs?
The iron panel will show a “storage pattern.”
↓ Iron (free iron is taken out of the blood to be stored)
↑ Ferritin (the iron is stored)
↓ TIBC (the transferrins are busy taking iron into storage)
Treatment?
Treat the underlying cause.
Inflammation
Hepcidin
Iron sequestered
Hepc-id-in
“HELPS IT IN” to the liver
THALASSEMIA
Globins are broken
Thalassemia refers to a problem with synthesizing globins. Thalassemia is typically genetic (autosomal recessive) and causes microcytic anemia. There is no cure, and the anemia is typically treated with blood transfusions as needed. On the blood smear expect to see target cells. Target cells are the opposite of spherocytes. Target cells have little cytoplasmic contents, resulting in a relative excess cell membrane (kind of like the excess skin after major weight loss). With too much floppy membrane, the RBC can’t maintain the classic bi-concave disc shape, rather it folds into the target shape instead. The iron panel is typically pretty normal. Interestingly, the RBC count (an often ignored lab value) is elevated and the RDW (a measurement of size variability) is low in thalassemia -- it’s like thalassemia makes the body pump out lots of small, identical RBCs!
There are 4 different genes for alpha globins. The four genes are usually written as “aa/aa.” Thus, there are 4 potential spots for mutations to occur. A mutation is usually written by replacing an “a” with a dash. Therefore, there are 4 alpha thalassemias. Each one is more severe than the previous (for example, aa/a- is much milder than a-/--).
A1 (aa/a-) refers to a single mutation of the alpha genes. Also called Alpha Thalassemia Trait. There are no symptoms.
A2 (aa/--) or (a-/a-) refers to two mutations. Also called Alpha Thalassemia Minor. Minimally symptomatic.
A3 (a-/--) refers to three mutations. Also called Hemoglobin Barts Disease, as this rare type of hemoglobin is found in abundance.
A4 (--/--) refers to four mutations. Also called Hydrops Fetalis, it causes universally lethal anemia and violent swelling in the fetus.
There are 2 different beta genes (ββ). Thus there are 2 beta-thalassemias.
B1 (b-) refers to a single mutation of the beta genes. Also called Beta Thalassemia Minor. It causes mild anemia.
B2 (--) refers to a double mutation of the beta genes. The beta globin is replaced by delta, which makes HbF. Causes profound anemia.
SIDEROBLASTIC ANEMIA
Sidero- (constellation) -blast (sprout)
Sideroblastic Anemia (SBA) refers to the microcytic anemia caused by a problem with synthesizing protoporphyrins. SBA can be caused by genetic mutations (Congenital SBA), environmental exposures (lead) or nutritional deficiency (B6 deficiency).
Congenital SBA can be either X-linked recessive (more common) or autosomal recessive. Usually due to a broken ALAS enzyme.
Lead poisoning causes sideroblastic anemia. It impairs the ALAD enzyme. Look for vague symptoms like fatigue, abdominal pain or confusion. Some rarer, but more specific signs, include bluish gum discoloration (Burton lines) or foot drop (fibular nerve lesion). Kids are more susceptible to lead, especially if they live in an old house built prior to the 1970s. Lead is also found in industrial settings, like factories or around car batteries.
Isoniazid is a drug that treats tuberculosis. It causes vitamin B6 deficiency, which can cause SBA.
Protoporphyrins are unusual box-shaped molecules that have an iron molecule in the center. They are an essential component of Hgb. Protoporphyrins are constructed by erythroblasts in several different steps, some of which occur inside the mitochondria while others occur outside. In SBA, there will be a buildup of unused iron. This surplus iron tends to clump up into little balls that form a ring around the nucleus. This is the key histologic finding in SBA, the ringed sideroblast. Note that they are only visible with a special stain for iron, called the Prussian Blue stain. Sometimes phagosomes full of tiny angular bits of iron can be visible on the usual H&E stain, and these are called Pappenheimer bodies (low yield). You can also expect to see some basophilic stippling, which represents clumps of abnormal ribosomes and RNA.
Lab Findings - This is an anemia (low H&H) that is microcytic (low MCV). There is a lot of unused iron in SBA; therefore, the iron panel will resemble iron overload (high iron, high ferritin, low TIBC).