Approaching Undifferentiated Anemia Beyond a CBC
A 67-year-old woman presents with progressive shortness of breath and fatigue, but routine labs reveal a hemoglobin of 9.2, hematocrit of 28%, and a mean corpuscular volume (MCV) of 84. What next?
Addressing borderline undifferentiated anemia cases like these requires a structured approach. Otherwise, you might miss impactful diagnoses.
“Anemia is certainly a critical topic for primary care clinicians because it’s super, super common,” says Dr. Michael Krug, clinical associate professor of medicine at the University of Washington School of Medicine and associate program director for the university's internal medicine residency program based in Boise, Idaho.
Anemia affects up to one-third of the global population. “You’re going to see anemia constantly,” Dr. Krug points out. “Having a rock-solid framework for how to move through things is just going to enhance your confidence and enhance the care for your patients.”
4 Anemia Mistakes That Derail Diagnosis
Dr. Krug identifies four of the biggest misconceptions and traps clinicians fall into when approaching anemia.
“If you screw up any of these four, your patients are really going to suffer for it big time, and not only short term but potentially long term,” he says. “You can majorly impact the trajectory of a patient’s health if you get some of these right.”
- Using serum iron to diagnose iron-deficiency anemia instead of ferritin and a percent solution. This approach can either overdiagnose or miss anemia altogether.
- Ruling out deficiency based on a borderline vitamin B12 level. When clinicians don’t follow up on borderline levels by issuing a methylmalonic acid (MMA) test or starting on vitamin B12, they risk serious patient consequences, including neurologic injury.
- Failure to follow up on a new iron deficiency anemia diagnosis with esophagogastroduodenoscopy, colonoscopy, or celiac disease testing. Without such tests, you aren’t investigating the root cause of the condition.
- Underusing serum protein electrophoresis (SPEP) or serum-free light chain testing in patients with undifferentiated anemia. Underuse can make it difficult to catch multiple myeloma in a timely manner.
Undifferentiated Anemia Demands a Structured Approach
That’s not to say an all-purpose, all-test approach is the right course of action for every patient. Primary care is full of pattern recognition problems, and undifferentiated anemia should be approached algorithmically. This way, you can cover common causes efficiently while keeping rarer but serious conditions on your radar.
“A structured approach to undifferentiated anemia is important in primary care today because it happens so frequently. You have to have a regimented answer to things and the next steps set in your mind,” says Dr. Krug. “You know you don’t have enough time to sit and ruminate and think every time you face anemia. You have to have it locked in.”
Here are four steps to take when dealing with undifferentiated anemia diagnosis.
Step 1: Review the Reticulocyte Index
Moving through tests step by step can improve your understanding of undifferentiated anemia. One of the first measurements to take is the reticulocyte count and reticulocyte index. “If it’s high, it’s hyperproliferative. Most commonly, it’s hypoproliferative or low,” explains Dr. Krug.
With that information, you can categorize the MCV and narrow down the diagnoses.
“If the MCV is less than 80, then you’re microcytic. You’re thinking of iron deficiency, thalassemia, and a few rare things,” he says. Iron deficiency is by far the most common, making up about 50% of all anemias, but it’s by no means the only diagnosis.
“If the MCV is between 80 and 100 normocytic, you’re thinking of anemia, of chronic inflammation, chronic kidney disease, multiple myeloma, and some other less common things,” says Dr. Krug.
“And then if you’re macrocytic, your MCV is over 100. Then you’re thinking vitamin B12 deficiency, folate deficiency, liver disease, alcohol use, or myelodysplastic syndrome,” he says. These vitamin deficiencies are more common in older adults, vegetarians, and pregnant women.
Step 2: Ask Patients the Right Questions
Before you begin testing, make sure to collect pertinent patient data and a complete medical history.
“The number one thing to ask about when you’re facing anemia is bleeding,” says Dr. Krug. “Bleeding is really important — especially taking a thorough menstrual history and not just saying, ‘Are your periods normal?’ Really get into how much is coming out, because it might be quite voluminous, but that might be normal to that patient.”
Other sources of bleeding, like GI blood loss, are less obvious but still relevant. NSAIDs, for example, are a common cause of occult blood loss. Patients tend to self-prescribe these over-the-counter meds, and they’re unlikely to report them unless asked directly. Even long-term low-dose use can lead to slow GI blood loss that’s sufficient to produce iron deficiency anemia.
“Does the patient have a history of bariatric surgery, especially gastric bypass surgery? Those patients are much, much higher risk for micronutrient deficiencies, so your thresholds for testing and treating are much lower,” says Dr. Krug.
Diet is another important area for anemia evaluation. “Ask if they eat a varied diet that includes eggs, meat, vegetables, and citrus fruits,” says Dr. Krug. “If they do eat all those things, then they’re much less likely to have a micronutrient deficiency in most clinical settings.”
Step 3: Order Tests That Matter
Dr. Krug lists three stages for investigating undifferentiated anemia. The first, at a minimum, “is a CBC [complete blood count] with a differential; a reticulocyte count so you can calculate the index; and an iron panel, including ferritin,” he says.
The next stage relies on earlier findings and suspicions. “The next level up is considering adding a vitamin B12 and a folate — especially if they have macrocytosis — and considering SPEP, serum-free light chains, especially if they have other symptoms or signs of something like multiple myeloma,” says Dr Krug.
“And then finally, if the patient has labs suggestive of a hemolytic anemia, then you would do a hemolytic anemia labs like total bilirubin, LDH [lactate dehydrogenase], haptoglobin, and a peripheral smear,” he says.
Step 4: Don’t Ignore Borderline Results
Even if the labs return as unremarkable, it might still be worth another look. Undifferentiated anemia is usually defined as hemoglobin levels <12g/dL in premenopausal women and <13 g/dL for men and postmenopausal women. Those thresholds vary, so borderline cases deserve attention.
“Either follow up borderline vitamin B12 with an MMA level and a homocysteine level, or just start empirically treating that patient with vitamin B12,” Dr. Krug says. “Otherwise, it will drift down, and then they’re going to get anemia and then major neurologic problems.”
Step 5: Match the Workup to the Patient
In theory, a sequential workup with follow-up labs will help you collect answers. But that won’t work for every patient, either financially or logistically. “For patients who I don’t think can or will come back, I have one shot, so I order the bulk of the work upfront because I really want to catch these high-yield diagnoses that we can make a major impact on,” says Dr. Krug.
Consider the patient’s personal ability to come in for a follow-up, as well as their availability for further care.
“At least in my community, the wait times for a hematologist for undifferentiated, low- to moderate-risk anemia, are very, very long,” Dr. Krug says. “So if you, as a generalist, can march through the first, second, maybe even third steps in the workup, you can really catch a lot of diagnoses yourself.
Set things up well so that all the basic stuff is covered and has been addressed before the patient reaches the hematologist,” Dr. Krug adds.
Catch the Nuances of Borderline Cases
The borderline case we introduced earlier didn’t have an obvious etiology based on history, but applying this structured approach to undifferentiated anemia would lead to a diagnosis.
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