Drugs, Alcohol, and Other Usual Suspects in Macrocytosis

This transcript has been edited for clarity. 
Matthew F. Watto, MD: Welcome back to The Curbsiders. I’m Dr Matthew Frank Watto, here with my great friend and America’s primary care physician, Dr Paul Nelson Williams. Are you ready to talk about macrocytic anemia? We had a great guest on this podcast, Dr Rakhi Naik. I learned so much from it. 
Paul N. Williams, MD: This was one of our live episodes, so the energy was palpable. 
Watto: We were at the esteemed institution of Johns Hopkins, and we got to talk about the Williams principle. What is the Williams principle? 
Willilams: The Williams principle is first, repeat the lab test. The joke is to keep repeating the test until you get the number you like. Lest I get sued, however, I should mention that this applies mostly to unexpected results. Often, particularly with some hematologic abnormalities, with a one-time recheck, you’ll see that the abnormality (for example, pseudothrombocytopenia) is fixed on repeat. A dip in hemoglobin, or leukocytosis, may resolve because something transient was happening. The CBC lends itself to the Williams principle of repeating the lab when something seems weird.
Watto: I completely agree with that. When the patient is asymptomatic and something is going on but it’s not too bad, I always repeat the lab at some point, depending on how worried I am about the finding. 
When you get a CBC and find macrocytosis, with or without anemia, it’s best to think about the mechanism. Something is causing a lot of young — Dr Naik used the word “juicy” — red cells, like a reticulocytosis. The marrow is sending out a lot of younger cells that are bigger on average, and that can result in macrocytosis. Or something is causing abnormalities to the cells; it could be lipid metabolism, or something wrong with red cell membranes, which happens in liver disease and alcohol use. It could be something that impairs DNA synthesis. VEXAS syndrome is even on the differential. So, the differential is pretty broad for macrocytic anemia. 
But Paul, if you’re working in primary care, what meds can cause macrocytosis? 
Williams: The big ones are methotrexate, HIV medications, and chemotherapeutic agents. There are a couple of less obvious ones; allopurinol, and even metformin to some extent, can lead to macrocytosis. I have a good chunk of patients on metformin who have also had macrocytosis, but I’m not sure I’d be brave enough to stop the medication to prove the concept. If it’s mild, I might feel better just blaming that.
Watto: When they’ve been on metformin chronically for a couple of years, patients can become B12 deficient. Dr Naik said that if she has a good reason to think a patient has B12 deficiency — such as having bypass surgery, or taking metformin or a proton pump inhibitor — she will send both B12 and methylmalonic acid levels. She sends them at the same time rather than in two steps if she has a high level of suspicion. I’m incorporating that into my practice as well. 
Dr Naik also said that if you are working someone up for anemia and sending a CBC, and you decide to follow the Williams principle, you should also send a reticulocyte count when you repeat the CBC to see whether it’s appropriate or inappropriate. She looks at the absolute reticulocyte count; you don’t have to calculate anything. 
I was happy to hear that because it’s a lot easier to interpret an absolute number rather than trying to calculate the index, which is something that I used to do back in my med student days. 
So, Paul, what other pearls were really helpful from this episode?
Williams: We had a discussion about alcohol use. It doesn’t take as much as you might think. Alcohol is an appealing mechanism to talk about because it hits many things. It can cause micronutrient deficiencies or hepatic injury, leading to macrocytosis. It can cause DNA damage and affect red cell metabolism. 
From a pathophysiologic standpoint, alcohol use hits you where it hurts, resulting in big red blood cells. So, revisit the patient’s history of alcohol use if you see macrocytosis.
Watto: I found a paper by Hoffbrand from 1997 that said even a few drinks, such as two gin and tonics a day, ingested chronically is enough to cause macrocytosis. When the drinking stops, it returns to normal in weeks to months. So, it is reversible, unless the patient has cirrhosis. 
Working up macrocytosis involves sending tests we are comfortable with. This is definitely well within our wheelhouse in primary care. But most people just jump right to let’s check for iron deficiency when a patient has anemia.
If the patient has macrocytic anemia, you should do the macrocytosis workup. That involves sending a metabolic panel. Look at the kidney and liver function, B12, and thyroid-stimulating hormone. If the patient is at risk for folate or copper deficiency, check for those things as well. Review the patient’s medication list. Take an alcohol use history. As internists, we can do all these things.
We also had great discussions on two other topics: hemolytic anemia and myelodysplastic syndrome. Click to hear the full podcast.