Reacting to CRP

In medicine, we often order tests reflexively, trusting that numbers will guide us toward truth. But what happens when a test is elevated — or completely normal — and the patient remains a mystery? In this episode, we explore C-reactive protein, a familiar marker that is often misunderstood. Through one challenging patient, we uncover what CRP truly measures — and what it does not. And in doing so, we are reminded that not all suffering can be captured in a laboratory value. 

Transcript

SPEAKER_01 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_04 0:31

Long time ago, in a teaching hospital far, far away. I was on the ward with Lauren, a brand new physician assistant who finished her program six months ago. We're reviewing a patient who is diagnostically challenging. This 62-year-old unhoused patient has been hospitalized for 32 days. He was admitted with generalized weakness. No obvious abnormalities were noted on all the investigations so far. When previous attendings tried to discharge him, the patient would report new alarming symptoms dizziness, blurred vision, chest pressure, palpitations, abdominal pain, constipation, then diarrhea, then bloody diarrhea, black stool, nausea, stuffy nose, hearing loss, dry skin, and of course, feeling unwell. I was the fifth attending physician. We reviewed all investigations together. None pointed to a clear organic cause. Lauren, who had been monitoring this patient for the last 30 days, seemed understandably frustrated. She sighed and asked, Dr.

SPEAKER_00 1:48

Kim, should we order a CRP?

SPEAKER_04 1:51

That's not a bad idea. Why do you want to order it?

SPEAKER_00 1:55

It's a marker of inflammation.

SPEAKER_04 1:57

Yes, that is correct. What cells make C reactive protein? Lauren, who had never worked with me before, looked puzzled at being asked such a question.

SPEAKER_00 2:08

Oh, I'm not sure. White blood cells.

SPEAKER_04 2:12

Actually, C reactive proteins are made in the liver by the hepatocytes. Lauren, you said C reactive protein is a marker of inflammation. But why is that?

SPEAKER_00 2:24

I'm not sure.

SPEAKER_04 2:25

Then let me ask you this. Should we also order C peptide or protein C?

SPEAKER_00 2:31

I don't think they're related.

SPEAKER_04 2:34

Correct. C peptide comes from insulin precursors. Protein C is a natural anticoagulant. So, Lauren, your reaction to my question about the C reactive protein suggests that you are not sure what C reactive protein reacts to. Lauren did not appreciate this etymologically well-crafted question. Regardless, we began our deep dive into one of the most reflexively ordered blood tests in medicine. CRP was discovered in 1930 while studying patients with acute pneumococcal pneumonia. Investigators noticed that the serum of very ill patients contained a protein that bound to the C polysaccharide of Streptococcus pneumonia. This C polysaccharide is a component of the pneumococcal cell wall. When patients recovered, the protein disappeared. They named it exactly what they observed, C reactive protein, a name fossilized in language. Importantly, the C does not stand for complement, cytokine, or cancer. It stands for the C polysaccharide. Only later did medicine realize that this same protein rises in many inflammatory states. So Lauren, do you know what CRP looks like? A puzzled look on her face. Lauren's CRP was rising along with cortisol. CRP is a pentamer. It is composed of five identical protein subunits arranged in a ring. This structure allows CRP to bind phosphocholine residues found on bacterial cell walls, such as Streptococcus or damaged or dying host cells.

SPEAKER_03 4:33

I see, Dr. Kim. This is why CRP is increased in inflammation. It binds to components of damaged or dying cell walls, but what does it do?

SPEAKER_04 4:44

CRP is a part of the innate immune system. As you noticed, Lorne, it binds the walls of bacteria and injured cells. This then activated the classical complement pathway, which leads to enhanced phagocytosis.

SPEAKER_03 4:59

I see. Then what causes the liver to make CRPs?

SPEAKER_04 5:04

Great questions. The instruction comes from cytokines, especially IL6, which is primarily produced by immune cells such as macrophages and T cells. One interesting contributor of increased CRP production is an organ that we used to think as inert and metabolically useless. Can you guess which one? The appendix. The appendix? Good guess, but no. Did you know that adipose tissue also release cytokines? Fat is not inert. Adiposecytes release interleukin 6. In fact, in obesity, a substantial proportion of adipose tissue cellularity consists of macrophages. In some parts approaching 30%, these macrophages also produce interleukin 6. This explains why obesity and metabolic syndrome are associated with chronically elevated CRP. Back when I was in medical school, which was in the last century, we thought of adipose tissue as inert and not much else. But now there is growing recognition that adipose tissue a low grade inflammatory state. Hence, CRP is raised in obesity. Studies show that individuals with a BMI greater than 30 tend to have significantly higher baseline CRP levels compared with normal weight individuals. Large population studies such as the Women's Health Study demonstrated a stepwise rise in CRP with increasing BMI, supporting the concept that obesity represents a chronic low-grade inflammatory state.

SPEAKER_03 6:51

So, Dr. Kim, when we measure CRP in the blood, does that measure free CRP or CRP bound to cells as well?

SPEAKER_04 7:01

Good question. The CRP test measures the CRP circulating freely in the blood. CRP that has already bound to bacteria or damaged cells usually gets cleared. So what we measure in the lab mainly reflects how much CRP the liver is producing at that moment. This is why we use CRP for tracking response to treatment in infections such as bacterial pneumonia or sepsis. Assessing inflammatory burden of disease such as inflammatory bowel disease or rheumatoid arthritis. So, Lauren, for our patient, let's order it and see what it shows. The next day, the CRP came back completely normal. Lauren looked relieved.

SPEAKER_03 7:54

Well, at least there is no inflammation.

SPEAKER_04 7:57

At that exact moment, the nurse paged us.

SPEAKER_02 8:00

Dr. Kim, the patient has a new symptom.

SPEAKER_04 8:04

What is it? I asked.

SPEAKER_02 8:06

He says he feels unwell. Pain everywhere.

SPEAKER_04 8:10

There was a pause.

SPEAKER_02 8:12

And it seems to get worse every time someone mentions the word discharge.

SPEAKER_04 8:18

Lauren slowly turned toward me. I looked at the CRP result again. Interesting, I said. The inflammation appears to be triggered by discharge planning. I paused, then added quietly, I know what you may be thinking, Lauren, but as healthcare professionals, the symptoms people feel should be considered always real. A normal CRP only tells us that the liver is not seeing the kind of inflammation it recognizes. It does not mean the patient is not suffering. Lauren nodded. Unfortunately, I added, there is still no blood test for every kind of suffering. I paused for a moment, then added one final thought for Lauren. CRP tells us when the body is inflamed, I said. But medicine still requires us to listen carefully for the illnesses that no molecule can measure.

SPEAKER_01 9:31

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