Anemia of Chronic Confusion

In this episode of The Clinical Etymologist, we explore a common clinical paradox—anemia in the presence of abundant iron. Through a real bedside conversation, we move beyond memorized lab patterns and uncover the physiology that explains them. What does it mean when ferritin is high, yet the patient remains anemic? Why does the body hide iron during inflammation, and what role does hepcidin play in this process? Together, we follow iron’s journey—from absorption to storage—and discover where the system breaks down. By the end, anemia of chronic disease will no longer be a pattern to memorize, but a story you understand.

Transcript

SPEAKER_02 0:10

You're listening to The Clinical Etymologist, a podcast where medicine meets meaning, created by Dr. Simon Kim, a general internist with a passion for the strange, fascinating, and sometimes hilarious roots of medical terminology.

SPEAKER_03 0:30

Long time ago, in a teaching hospital far, far away.

SPEAKER_00 0:36

I was on the weekend covering the clinical teaching unit. I had a 30-year medical student with me, a keen Padawan named Alex. Bright and thoughtful, and she was the kind of student who still believes that medicine is a noble calling. She told me she had applied to internal medicine. Alex, I said, why did you apply to infernal I mean internal medicine? She smiled politely. A good sign.

SPEAKER_03 1:07

Well, I love physiology and how we can use it to make diagnoses and guide treatment.

SPEAKER_00 1:13

I see. Any thoughts on subspecialty? She hesitated.

SPEAKER_03 1:19

Maybe hematology, uh but I'm not sure.

SPEAKER_00 1:22

Excellent, I said. Uncertainty is the first step towards wisdom. Why don't you start rounding on your patients and I'll join you shortly? Off she went. And I did what good staff physicians do in moments of pedagogical responsibility. I grabbed a large double double and retreated to the staff wellness room. I like to plan my teaching over coffee. What should I teach her today? Something foundational. Something memorable. Something that might keep her in internal medicine at least for another year until she matched. A documentary was playing Wildlife in Northern Canada. A polar bear appeared. Majestic, powerful. And without warning, my mind drifted. A teaching opportunity about polar bear liver. Yeah. Vitamin A. Yeah, and the toxicity, the hepatotoxicity, and increased intracranial pressure. Then a moose emerged from the forest. And again my mind wandered. Iron! Look at that meat! The moose meat, gram per gram, contains among the highest iron content of any commonly consumed meat. Then I saw the salmon. I braced myself for omega-3 fatty acid pathway, but before my mind could complete the metabolic pathway, my pager went off. Alex was ready.

SPEAKER_03 3:08

Mrs. Payne is an 82-year-old who presented with pylonephritis. Her culture grew E. coli. She is responding well to ceftriaxone. Her vitals are stable, no fever today. White blood cell count is trending down, and her hemoglobin is stable at 100, which I think is due to chronic inflammation. Electrolytes and renal function are good. She should be ready to go home in a day or two.

SPEAKER_00 3:34

Sounds good, Alex. But one question. She is anemic, and you said it is due to chronic inflammation. How do you know that?

SPEAKER_03 3:44

Well, she reports no bleeding symptoms. She has diabetes and osteoarthritis. And her hemoglobin has been low for at least five years.

SPEAKER_00 3:54

Good. That supports your thinking. But how do we confirm it?

SPEAKER_03 4:00

We could do iron studies. Well, ferritin T IBC transferrin saturation.

SPEAKER_00 4:05

And what would you expect?

SPEAKER_03 4:08

High ferritin, low TIBC, low transferrin saturation.

SPEAKER_00 4:14

You are correct. I paused. Now tell me, what is ferritin?

SPEAKER_03 4:19

It's an iron storage protein. We use it to measure iron storage. And it also goes up in inflammation.

SPEAKER_00 4:27

Good. And why does ferritin go up in inflammation?

SPEAKER_03 4:32

Well, it is a cute phase reactant. I know it goes up, but as to why I am not sure. I remember something about decreasing iron availability to bacteria.

SPEAKER_00 4:42

Good. You're close. I leaned slightly forward with hands in the air for dramatic effects. If ferritin is an iron storage protein and its level goes up, how does that decrease iron availability where there is more of it in the blood?

SPEAKER_03 5:00

Hmm, I'm not entirely sure. I just memorized the patterns for iron deficiency anemia.

SPEAKER_00 5:08

That is entirely acceptable. Memorizing is good, but understanding and integrating is even better. So to understand the anemia of chronic confusion, I mean inflammation one must start with a protein. Have you heard of liver expressed antibacterial protein one? Alex shook her head. You have, I paused. Just by a different name. It is the Hepsidin. Alright, Alex, let's build this from first principles. Let's start with iron. Tell me how iron is absorbed into our body.

SPEAKER_01 5:52

Okay, Dr. Kim, we take iron through diet. In the acidic environment of the stomach and proximal small bowel, iron becomes absorbable and enters the enterocyte. Then it is transported to the liver or bone marrow.

SPEAKER_00 6:08

Excellent. Once iron is inside the enterocytes, it has to get rid of it quickly. There is a specific exit door for the iron. Do you know what that door is called?

SPEAKER_01 6:19

Not sure.

SPEAKER_00 6:21

Well, it is named after what it does. Ferro meaning iron and portin, a door. Ferroportin. And this is present on enterocytes as well as on hepatocytes and macrophages, so that irons can pass through them. Now, what transfers iron from enterocytes to other cells?

SPEAKER_01 6:42

I know this one. It's transferrin.

SPEAKER_00 6:46

Exactly, the transferrin transfers two iron atoms. Fun fact, cirilloplasmin, which contains copper, oxidizes iron from iron two plus to iron three plus so that it can bind to transferrin. This iron bound transferrin then unloads iron at hepatocytes or macrophages. Alex, how does iron actually get into those cells? I don't know, doctor Kim. Not through the ferroprotein. That is only the exit. It enters through a different door, the transferrin receptor. Alex looked very curious now. The transferrin binds to its receptor on the cell surface. The whole complex is pulled inside, and in an acidic compartment, iron is released and enters the cell. Think of it this way the truck docks gets pulled into the warehouse and unloads its cargo. Once delivered, iron is stored inside cells in a protein called ferritin, an iron basket that can hold up to 5,000 iron atoms. With inflammation, the liver produces a protein called liver-expressed antibacterial protein one, also known as heptidin. What do you think it does?

SPEAKER_01 8:15

I am not sure, Dr. Kim.

SPEAKER_00 8:18

Neither were the scientists who first discovered it. They thought this protein had some antibacterial property first. Then later they found out that it has a significant role in iron metabolism. Mainly, uh hepsidin binds ferroportin and causes it to be internalized and degraded. So iron cannot leave cells. It becomes trapped.

SPEAKER_01 8:43

I see. Is that why in inflammation transferrin levels fall? As there is less iron being transferred between cells?

SPEAKER_00 8:51

Yes. Transferrin falls in inflammation because it is a negative acute phase reactant, and also because iron trafficking is reduced. Now, that leaves us with the question of why ferritin is high in inflammation. Any thoughts?

SPEAKER_01 9:08

I am not sure, and this has been the reason for confusion. Ferritin is the iron storage protein. In inflammation, our body tries to reduce availability of iron to bacteria. But if ferritin level is increased in the blood, doesn't that mean there is more iron in the blood? Wait, wait. Is the ferritin we measure in the blood the same as the ferritin inside cells?

SPEAKER_00 9:34

Her eyes widened. Bingo. Yes. The ferritin we measure in the blood is not the same as the ferritin in the cells. It is a degraded secreted fragment of intracellular ferritin. It is a surrogate, a reflection of how much iron is being stored inside macrophages and hepatocytes. Serum ferritin is not a container, it is a signal. So high ferritin in the blood does not mean iron is available. It means iron is being sequestered. In anemia of chronic inflammation, the RBCs are typically normacytic. It may become mildly microcytic due to relative iron deficiency, but does not become significantly microcytic as in anemia of iron deficiency. So, Alex, how does one differentiate these two anemias?

SPEAKER_01 10:35

I look at several parameters. If ferritin is low, that strongly indicates iron deficiency. If ferritin is high, it could reflect inflammation, with or without true iron deficiency. In that situation, transferrin helps. It is typically high in iron deficiency, as the body upregulates transport to capture more iron. In inflammation, transferrin is low.

SPEAKER_00 11:02

Good. Very good. What about iron saturation? Does that help? Alex thought for a moment.

SPEAKER_01 11:09

It can help, but not perfectly. In iron deficiency, transferrin is high and iron is low. So saturation becomes quite low, often below 15%.

SPEAKER_00 11:21

And in inflammation?

SPEAKER_01 11:23

Transferrin is low, and iron is also low, so the saturation can still be low or low normal, typically in the fifteen to twenty percent range.

SPEAKER_00 11:34

Exactly. If ferritin is low, you have your answer. But if ferritin is high, I looked at her. You must think. I paused. In iron deficiency the problem is lack of iron. In inflammation, the problem is lack of access.

SPEAKER_02 12:08

As a novice podcaster, Dr. Kim, despite his busy schedule, is still constructing the official website where you'll be able to subscribe, leave a review, explore show notes, and connect further. But that will come soon. Stay tuned. Until next time, channel your inner etymologist because every diagnosis has a backstory and every word has a pulse.