AssessmentsAnemia: Clinical practice
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USMLE® Step 2 style questions USMLE
A 55-year-old woman comes to the clinic with generalized fatigue, unsteady gait, and numbness in her lower limbs for the past 2 months. She states that she often experiences a “tingling” sensation in her legs and feet. Her other medical conditions include hypertension and hypercholesterolemia, which are managed with hydrochlorothiazide and atorvastatin, respectively. She had a gastric bypass surgery one year ago. Temperature is 37.0°C (98.6°F), pulse is 96/min, respirations are 18/min, and blood pressure is 136/95 mmHg. She is oriented to time, place and person but is slow to respond to questions. Motor strength is 4/5 in bilateral lower limbs, and deep tendon reflexes are diminished at the ankles. Sensory loss is noted in the bilateral feet with diminished perception to touch and vibration. The patient’s gait is ataxic. Romberg test is positive. Bilateral plantar reflexes are upgoing. Complete blood count reveals a hemoglobin of 10 g/dL. Peripheral smear is shown below:
Reproduced from Wikipedia
Which of the following is the next best step in evaluation?
Content Reviewers:Rishi Desai, MD, MPH
Anemia is a blood disorder where the body doesn’t have enough healthy red blood cells or hemoglobin, resulting in poorly oxygenated tissues throughout the body. This condition takes many forms, ranging from mild to severe depending on the cause.
Anemia in males is a hemoglobin below 13.5 g/dL or a hematocrit less than 41%, and in females it’s a hemoglobin below 12.0 g/dL or a hematocrit less than 36%, but those numbers can differ based on which guidelines you’re using. Also, people with chronic respiratory diseases like emphysema or medical problems like malnutrition may have symptoms of anemia even at normal levels of hemoglobin and hematocrit. In addition, those living at altitude can have high levels of hemoglobin and hematocrit to help deal with the lower oxygen levels. So it’s good to keep in mind that these guidelines aren’t appropriate for everyone. Now, the most common signs and symptoms of anemia are dyspnea with exertion and at rest, fatigue, pallor, and a hyperdynamic state like bounding pulses and palpitations.
If someone is anemic, the first thing to look at is the mean corpuscular volume or MCV. An MCV of less than 80 femtoliters is low, so microcytic, between 80 and 100 femtoliters is normal, so normocytic, and above 100 femtoliters is high, so macrocytic. Of course, some individuals might have a few types or causes of anemia mixed together, and that’s where things get more complicated. Most microcytic and macrocytic anemias are caused by a problem in producing either red blood cells or hemoglobin, and in those situations we can measure the reticulocyte production index (RPI) or corrected reticulocyte count (CRC). This number is the percentage of red blood cells that are reticulocytes, or immature, and is normally between 0.5 and 2.5%. A person with anemia and less than 2% RPI means that their body is not capable of producing enough red blood cells. In certain normocytic anemias that are caused by the loss or destruction of red blood cells, the RPI is above 2% because the body increases red blood cell production to replace the ones that were lost.
Now, microcytic anemia can be divided into four main types - iron deficiency anemia, anemia of inflammation & chronic disease, thalassemias, and sideroblastic anemia. To distinguish them, you should check iron studies which includes the serum iron, which is the free iron in the blood, the total iron binding capacity or TIBC, which tells you how much unbound transferrin is floating around and is available to bind iron, the ferritin level, which tells you how much ferritin is floating around and already bound to iron - effectively storing it, and a peripheral blood smear.
Iron deficiency anemia is most common and usually there’s a low serum iron, high TIBC, and a low ferritin. Low serum iron means that there’s more unbound transferrin, so there’s increased total iron binding capacity, and that there’s less ferritin that’s already bound to iron and storing it. This generally occurs in people with chronic slow bleeding - where the iron in the red blood cells is lost instead of getting recycled. This includes women with frequent or heavy menstruation or patients with colon cancer, which should be ruled out in older men through fecal occult blood testing. Another cause is pregnancy, due to increased iron requirements for fetal development. In some settings, iron deficiency anemia can be the result of not having enough iron in the diet. Treatment for iron deficiency anemia includes addressing the cause and giving oral iron supplements, which can be taken with orange juice which is slightly acidic and can help absorption. Common side effects of oral iron include nausea, diarrhea, and constipation. If oral iron isn’t effective, or the side effects can’t be tolerated, IV iron can be used instead. Sometimes, the cause of refractory iron deficiency is a Helicobacter pylori infection, because the bacteria can sequester iron and it can cause gastric bleeding, or inflammatory bowel disease or celiac disease, both of which can cause malabsorption.
In anemia of chronic disease, there’s low serum iron, low total iron binding capacity, and high ferritin. This basically happens because there’s a lot of inflammation, and during periods of extended inflammation the body likes to store away iron. Anemia of chronic disease often develops in people with chronic inflammatory diseases, like infections, autoimmune disorders, and various cancers, and typically resolves once the underlying condition resolves.
Next, there’s thalassemia, where everything may be normal in mild cases - so normal serum iron, normal total iron binding capacity, and normal ferritin - while individuals with more severe disease have elevated serum iron, decreased total iron binding capacity, and elevated ferritin. This is because the problem has to do with making the globin chains of hemoglobin. There are two types of thalassemia: alpha and beta. In alpha thalassemia, there is a mutation in the alpha globin genes that code for alpha globin chains, which are present in both fetal and adult hemoglobin, while in beta thalassemia, there is a mutation in the beta globin genes that codes for the beta globin chains, which are only present in adult hemoglobin. There are four alpha globin genes, and two beta globin genes, so if more genes are defective, then fewer normal globin chains are produced, and the more severe the thalassemia is. If there’s one defective alpha globin gene, there are usually no symptoms. If there are 2 defective alpha globin genes or one defective beta globin gene, then half of the genes are gone and there are mild symptoms.
Three defective alpha globin genes or two defective beta globin genes may result in mild symptoms in some individuals, while in others it can lead to severe disease. And if all four alpha globin genes are defective, that’s incompatible with life, and the fetus usually dies in utero; whereas beta thalassemia is not lethal in utero because the fetal hemoglobin does not contain beta globin chains. To figure out which chains are missing, you can use hemoglobin electrophoresis. Usually, patients with mild thalassemia don’t need treatment, while patients with severe thalassemia are treated with blood transfusions. The dependency on blood transfusions for survival makes all subtypes of alpha and beta-thalassemia fall into two clinically-relevant categories. These are transfusion-dependent thalassemias, covering all the subtypes requiring blood transfusions for survival; and non-transfusion-dependent thalassemias that do not require transfusions for survival. To prevent transfusion-related iron overload, people with transfusion-dependent thalassemias are given iron chelating agents that trap some excess iron and sweep it away through feces or urine.
In sideroblastic anemia, there’s high serum iron, low total iron binding capacity, and high ferritin level. It is characterized by sideroblasts, which are basically immature red blood cells found in the bone marrow. These erythrocytes cannot utilize iron for the synthesis of heme, so iron accumulates inside the mitochondria surrounding their nucleus, forming a ring. Eventually, unused iron builds up in the blood and binds to the transferrin proteins, causing a low total iron binding capacity. Increased serum iron also leads to increased ferritin levels. Some causes of sideroblastic anemia are congenital, like genetic mutations, whereas others are acquired like myelodysplastic syndrome, excessive alcohol use, copper or vitamin B6 deficiency, or intake of certain antimicrobial drugs. Diagnosis is based on bone marrow biopsy, which shows ringed sideroblasts when stained with prussian blue, a pigment that binds to iron. For congenital cases, there might be genetic testing. Treatment depends on the cause and could include stopping the use of alcohol or medication, if that’s the cause. Some congenital cases respond to vitamin and mineral supplements, and in the case of myelodysplastic syndrome, it requires a bone marrow transplant.
Now, if a person has macrocytic anemia, the next step is asking for a blood smear to figure out whether it’s megaloblastic or non-megaloblastic. Megaloblastic anemia is more common, and it’s caused by impaired DNA synthesis during red blood cell production, which leads to continuing cell growth without division. On a blood smear there are larger-than-normal red blood cells and hypersegmented neutrophils, which means they have 6 or more lobes in their nucleus when they normally have just three or four. The two main causes of megaloblastic macrocytic anemia are vitamin B12 and folate deficiency, so blood levels of both should be checked to see if either one is low. If these two are not informative enough, also the blood levels of homocysteine and methylmalonic acid may be checked. Homocysteine is generally elevated with either deficiency, while methylmalonic acid is elevated when B12 is low, but it’s normal when folate is low.
B12 is found in animal protein and can be stored for three to ten years in the liver. So people who avoid all animal products - like long time vegans who don’t take B12 supplements - can get B12 deficiency, that would be a big missed steak. And even if someone does eat meat they can still get B12 deficiency, if they’re not absorbing it properly. Normally, meat or dairy are broken down in the stomach and the B12 is released. Next a protein made by parietal cells in the stomach called intrinsic factor binds to the B12. Then, the B12-intrinsic factor complex moves all the way through the intestines to the terminal ileum, where special cells recognize intrinsic factor and absorb the whole complex. Now, various things can go wrong with this process, and that would cause B12 levels to fall. In pernicious anemia, IgA antibodies attack intrinsic factor or the parietal cells, and either way, it interferes with intrinsic factor’s ability to bind to B12, and subsequently get absorbed. In Crohn's disease, often the terminal ileum gets damaged. In people that get a gastric bypass, the ingested food passes through the stomach quickly, so even if intrinsic factor is produced, it can’t get to the food to bind B12.
Now, B12 is used throughout the body, so people with B12 deficiency develop a variety of neurologic symptoms. After confirming that there’s a B12 deficiency, further testing should be carried out to figure out the cause, for instance by looking for anti-intrinsic factor antibodies for pernicious anemia, or carrying out endoscopic or imaging studies in patients that might have Crohn’s disease. When the cause of B12 deficiency is a dietary problem, it’s treated with oral B12 supplement. When the problem seems to be absorption related, it could be treated with really high oral B12 doses - higher than 1000 µg to allow for passive diffusion in the gut - or with intramuscular B12 injections weekly to get the level back up and then monthly, and then this can be followed by oral supplementation if needed.