Microcytic anemia: Pathology review

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Case Study0:00–0:36

At the Family Medicine Center. There is a 60 year old indigenous American named is two who came to visit the doctor because of his progressive fatigue and difficulty in swallowing.
Next to him, there is a mother from Greece with her child Thalia who was 10 months old. Little Thalia appeared healthy at birth.
But in the past two months, her mother noticed that her face was often pale. She's been less active and there was a mass in her belly.
Both E two and pea are suffering from anemia, which is defined as lower than average levels of hemoglobin, typically below 13.5 g per deciliter in adult men and below 12.0 g per deciliter in adult women for Children.

Pathology0:36–2:00

This level varies based on the age. Now, anemias can be broadly grouped into three categories based on mean corpuscular volume or M CV, which reflects the volume of a red blood cell or RBC.
So, microcytic anemia is where the MCV is lower than 80 femtolitre. Normocytic with an M CV between 8100 femtolitre and macrocytic with an M CV, larger than 100 femtolitre.
Now, let's focus on the microcytic anemias and the most common causes are iron deficiency anemia, lead poisoning, sideroblastic anemia and thalassemias.
Although microcytic anemia can also present in anemia of chronic disease, which is caused by inflammatory conditions like rheumatoid arthritis and systemic lupus erythematosus or sle it's usually classified as a normocytic anemia.
Now, iron deficiency anemia, lead poisoning and sideroblastic anemia are caused by defective heme synthesis. While thalassemias are caused by defective globin chains.

Hemoglobin Synthesis2:00–2:37

Normally RBC S are loaded with millions of copies of a protein called hemoglobin. Hemoglobin is actually made up of four peptide or globin chains.
Each bound to a heme group. Those four he molecules have right in the middle iron which binds to oxygen and allows it to move in our body.
Ok. So let's look at iron deficiency anemia which could be caused by decreased intake, decreased absorption, increased demand or increased loss of iron for your exams.

Iron Deficiency2:37–5:54

It's important to know that the clues to help you identify this disorder are often based on the patient's history. The most common cause of iron deficiency is chronic blood loss.
This includes women with heavy menstruation or people with bleeding gastric ulcers. And most importantly, elderly males with colon cancer that can bleed.
Another cause of iron deficiency is decreased absorption. The duodenal cells are normally responsible for the absorption of iron which is present in two forms in our diet.
The heme iron and the nonheme iron. The heme iron is in the ferrous or fe two plus state and can be directly absorbed.
But the nonheme iron is in the ferric or fe three plus state and needs to be reduced to heme iron first before being absorbed.
So the stomach's hydrochloric acid activates a group of enzymes in the duodenal cells collectively called ferrireductase which reduces fe three plus to fe two plus.
Ok. So, decreased iron absorption can occur with inflammation and destruction of duodenal cells like an inflammatory bowel disease or celiac disease or with decreased stomach acid production like after a gastrectomy where a part of the stomach is removed.
Next malnutrition, which sometimes happens with infants and vegans and increased iron demand like during pregnancy can also cause iron deficiency anemia.
So whatever the cause, we end up with a decrease in the body's iron stores leading to decreased heme synthesis. And normally there's a low level of free erythrocyte protoporphyrin or F EP in red blood cells.
Since this is a precursor to heme. So when there is a defect in heme synthesis, these precursors build up and it's a good indicator for iron deficiency.
The peripheral blood smear shows RBC S that are microcytic since there's not enough hemoglobin for a normal sized RBC and the bone marrow starts pumping out smaller cells.
They are also hypochromic since they contain less hemoglobin and look more pale. Ok.
Another important fact is that the red blood cell distribution with or RDW is high. This is because we get a mix of normal sized cells from before the iron deficiency and newly produced microcytic cells.
Ok. Moving on if someone is chronically exposed to lead, usually Children ingesting lead containing paint chips or adults who inhale lead while working in mines or industry, they can get lead poisoning.

Lead Poisoning5:54–7:20

Lead inhibits delta aminolevulinic acid or delta ala dehydratase and ferrochelatase. Two important enzymes in the heme synthesis pathway.
It's important to remember that lead also inhibits R RNA degradation causing old Rrna to accumulate inside the RBC S forming tiny aggregates that are dispersed throughout the cytoplasm.
And this is referred to as sting. Once again, this affects heme synthesis.
So free erythrocyte protoporphyrin or F EP builds up on a peripheral blood smear. These aggregates stain blue.
So they are basophilic and we call this basophilic stippling. Now, just like iron deficiency anemia, there's a decrease in hemoglobin synthesis.
So we get microcytic and hypochromic RBC S. The RDW is high because we also get a mix of normal size cells produced before the lead poisoning and newly produced microcytic cells.
Next up is sideroblastic anemia where cro means iron and refers to iron accumulation in the mitochondria. And blast refers to the nucleated precursors of RBC S called erythroblasts.

Sideroblastic Anemia7:20–9:38

Sideroblastic anemia can be genetic or acquired x linked defect in ala synthase gene is a genetic cause. A A synthase normally catalyzes the first reaction in the heme biosynthetic pathway and a defect in this enzyme prevents iron from being incorporated into heme and they build up in the mitochondria.
The acquired causes include pyridoxine or vitamin B6 deficiency. Since ala synthase uses vitamin b6 as a cofactor for your exams.
Vitamin B6 deficiency commonly occurs as a result of isoniazid which binds and inactivates. Vitamin B6.
Myelodysplastic syndrome is an acquired cause of sideroblastic anemia where the blood forming cells in the bone marrow do not mature normally and become dysplastic.
It's important to know that this increases the risk of developing hematological malignancies like acute myeloid leukemia.
Other acquired causes include chronic alcohol use, lead poisoning, vitamin b6 deficiency, copper deficiency and drugs like isoniazid and chloramphenicol.
Remember for your test that these are reversible causes on a peripheral blood smear. We get microcytic hypochromic rbcs and basophilic stippling.
So it's similar to lead poisoning. However, the specific test to use is the Prussian blue stain on a bone marrow biopsy specimen which shows the iron laden mitochondria forming a ring around the nucleus giving the classic ringed sideroblast appearance.
Finally, the RDW is high as we get a mix of normal sized cells and newly produced microcytic cells. Ok.
Moving on to thalassemias where there's a deficiency or absence in the production of the globin chains of hemoglobin hemoglobin A or HBA made up of two alpha globin and two beta globin peptide chains makes up approximately 97% of the total hemoglobin in adults hemoglobin A two or HBA two, which is made up of two alpha globin and two delta globin chains makes up approximately 2.5% of total hemoglobin.

Globin Chain Synthesis9:38–10:44

Now, hemoglobin F or HB F made up of two alpha globin and two gamma globin peptide chains is the primary hemoglobin of the fetus but makes up less than 1% in adults.
In alpha thalassemia, there is a mutation in the genes that code for alpha globin chains. While in beta thalassemia, there was a mutation in the genes that code for the beta globin chains.
Now, in alpha thalassemia minima, there's one defective alpha gene usually causing no symptoms in alpha thalassemia minor.

Thalassemia10:44–16:35

There are two defective alpha genes causing mild microcytic hypochromic anemia. This can either be caused by a cyst deletion where mutated genes are on the same chromosome or a trans deletion.
When the mutated genes are on two different chromosomes, cyst deletion variants are more prevalent in Asian populations.
Whereas trans deletion variants are more prevalent in African populations. If three alpha genes are defective, it is hemoglobin h disease or HBH with moderate to severe microcytic hypochromic anemia.
And if all four alpha genes are defective, it's called hemoglobin Barts disease or HB Barts and the fetus usually dies in utero peripheral blood smear shows microcytic hypochromic rbcs.
Now, when beta globin chain is under produced, we have beta thalassemia minor which is usually asymptomatic when beta globin chain is absent.
This is called beta thalassemia major and causes severe microcytic hypochromic anemia which is not lethal in utero. As the fetal hemoglobin does not contain beta chains.
So in beta thalassemia, major HB F is protective and the disease becomes symptomatic only after six months when HB F declines.
Now, the absence of betaglobin leads to hypoxia because there is fewer HBA to carry oxygen to organs and tissues. To compensate.
These individuals rely on the bone marrow to produce more red blood cells. A high yield fact is that if they get infected with parvovirus B 19, this may suppress red blood cell production in the bone marrow which can cause a life threatening aplastic crisis.
Important facts to remember for exams is that HBA two is elevated in beta thalassemia, both minor and major to compensate for the decreased synthesis of HBA.
A hint the test makers could give is that the disease is more prevalent in the mediterranean population, peripheral blood smear and beta thalassemia major shows target cells and sometimes increased anisopoikilocytosis, meaning variation in size and shape of RBCs X ray of the skull might demonstrate a crew cut or hair on end appearance due to bone marrow expansion.
Now, in all thalassemias, the RD W is normal, reflecting the uniformity of RBC small size. However, in beta thalassemia major RD W can be high due to anisopoikilocytosis.
Another key concept you'll need to know is that they are diagnosed via hemoglobin electrophoresis. In beta thalassemia minor HBA two is greater than 3.5% while in beta thalassemia major, the increase in HBA two is greater along with an increase in HB F.
Now, some individuals are HB S beta thalassemia, heterozygotes. What this means is that they have one beta globin gene with the sickle cell disease mutation, which encodes for an abnormal adult hemoglobin called hemoglobin S for sickle or HB S and one with a beta thalassemia mutation depending on the type of beta thalassemia mutation.
People may have no normal hemoglobin called sickle beta zero thalassemia or a reduced amount of normal hemoglobin called sickle beta plus thalassemia.
In any case, when there's acidosis, hypoxia or dehydration, HB S changes its shape and aggregates with other HB S proteins to form long chains that distort the RB C into a crescent shape that looks like a sickle, sickled RBC S get stuck in capillaries and that leads to tissue ischemia and pain.
Oftentimes it's an emergency called sickle cell crisis or vasoocclusive crisis, peripheral blood smear will reveal sickle shaped cells.
But diagnosis is made via hemoglobin electrophoresis. In a newborn with sickle beta zero thalassemia, it will show an intense band of hemoglobin F or HB F and another lighter band of H BS.
Instead of the adult hemoglobin A or HBA, a newborn with sickle beta plus thalassemia will have an HB F as well as an HBs and a light HBA.
A band. If newborn screening is not done, then the diagnosis is made during a sickle cell crisis.
In this case, a healthy individual would have an intense band of HBA. An individual with sickle beta zero thalassemia would have an intense band of H BS and an individual with sickle beta plus thalassemia would have an HBs band with a light HBA band.
Also, it's important to note that for clinical purposes, all the phenotypes of both alpha and beta thalassemias fall into two categories based on the dependency on blood transfusion for survival.

Symptoms16:35–18:41

First, there is transfusion dependent thalassemia or T DT, which covers all the subtypes that require regular blood transfusions for survival.
This category includes beta thalassemia, major symptomatic beta thalassemia, intermedia severe HBH disease and surviving HB Barts, hydrops, fetalis.
On the other hand, the nontransfusion dependent thalassemia or NTD T refers to the thalassemias that do not require regular blood transfusions.
This category includes beta thalassemia intermedia and non severe HBH disease. Now, all anemias can present with fatigue, pallor and shortness of breath.
But other symptoms can help you identify the specific disease for iron deficiency anemia. There's Corchia or spoon nail where the nails become flat or even concave.
Next is pika, which is the consumption of nonfood substances like ice hair or dirt and glossitis. Plumber.
Vinson syndrome is also associated with iron deficiency and presents with chilosis and dysphagia due to esophageal webs.
Lead poisoning can present with abdominal pain or colic constipation and in severe cases with neurologic signs due to encephalopathy, wrist and foot drop due to peripheral neuropathy can also occur and patients can also have blue lead lines or bluish pigmentation at the junction of the teeth and gingiva.
Now, in beta thalassemia, major patients can have skeletal deformities caused by bone marrow expansion. This leads to chipmunk facies, meaning enlarged forehead and cheeks.
Now, the body will also undergo extramedullary hematopoiesis where the liver and spleen will try to produce extra red blood cells.

Iron Studies18:41–20:16

And this can cause hepatosplenomegaly HBs, beta thalassemia, heterozygotes have mild to moderate sickle cell disease symptoms.
These include acute complications like sickle cell crises causing a variety of problems like avascular bone necrosis, stroke, acute chest syndrome, renal dysfunction and priapism.
Another acute complication is splenic sequestration. Chronic complications include growth and developmental delay learning and behavior issues, pulmonary hypertension and chronic kidney disease.
Now, it's important to remember the iron studies values since they might be the best clues for identifying the cause of a microcytic anemia.
Iron studies include serum iron ferritin, a marker of iron stores transferrin a molecule that transports iron in the blood and T IBC total iron binding capacity, which indicates the amount of unbound transferrin in the blood.
Now, in iron deficiency, there's low serum iron. So there's nothing to store, meaning low ferritin.
Now remember that ferritin is an acute phase reactant. So it could be elevated during infections and chronic illnesses.
The liver makes more transferent since the body wants to shuttle as much of the available iron as possible. And since there's so little iron, the T IBC is increased in sideroblastic anemia, there's plenty of iron but it can't be used to make him.

Treatment20:16–21:00

So there's high serum iron, high ferritin, but normal or low transferrin and T IBC in thalassemias, there's high serum iron, high ferritin and low transferrin.
And T IBC iron overload occurs in thalassemia due to ineffective erythropoiesis. And from the multiple blood transfusions used to treat the disorder in lead poisoning.
Iron studies are normal. All right.

Review21:00–21:43

Now, treatment for iron deficiency anemia includes addressing the cause and giving oral iron supplements for lead poisoning.
First line treatments include chelating agents which trap free lead and sweep it away through feces or urine. These are dimer capr and EDTA for adults and succimer for Children.
For sideroblastic anemia. Treatment involves removal of toxins if there are any and administering pyridoxine.
Finally, patients with mild thalassemia don't need treatment while patients with severe thalassemia are treated with blood transfusions.

Summary21:43–23:18

All right, it's a quick recap microcytic anemias can occur when there's a problem in synthesizing. One of the two main components of hemoglobin heme and the globin chains.
There are many disorders that affect heme synthesis and iron deficiency anemia is the most common sideroblastic anemia and lead poisoning also fall under this category.
Thalassemia. On the other hand affects globin chain synthesis and could be alpha or beta depending on which type of globin chain is affected.
A diagnosis can be made based on iron studies and electrophoresis, but also consider the other symptoms and lab findings.
Now, back to the patients due to his age, he's two most likely has iron deficiency anemia due to colon cancer. He also has plummer Vinson syndrome which is causing his dysphagia.
This can be confirmed with iron studies and it's important to order a colonoscopy to check for colorectal carcinoma. Meanwhile, Thalia probably has beta thalassemia as symptoms started six months after birth due to the decline in HB F.
Another hint is that this disorder is more prevalent in the Mediterranean population. Like the Greeks, the mass in her belly is due to hepatosplenomegaly and the hemoglobin electrophoresis will confirm the diagnosis.