Inflammation-Mediated Dysregulation of Iron Homeostasis and Its Association with Anaemia Severity in Hidradenitis Suppurativa: A Cross- Sectional Study with Mediation Analysis

Chronic inflammation is a state where the body's immune system remains in a constant, low-level alert, often triggered by persistent infections or autoimmune conditions. When this happens, the body produces signaling proteins that act as alarms, telling other parts of the immune system to stay on high alert. One of the most common ways doctors measure this internal fire is by looking at a protein called C-reactive protein, or CRP, which rises in the blood when inflammation is active. While this fire is meant to protect the body, it can sometimes cause unintended damage to other systems, including the production of red blood cells. Red blood cells are the vehicles that carry oxygen throughout the body, and when their numbers drop, a person develops anemia, a condition that causes fatigue and weakness. In many long-term inflammatory diseases, the body struggles to use the iron it has, locking it away in storage so that new red blood cells cannot be built, even though the total amount of iron in the body might be normal.

A new study focused on a painful skin condition called hidradenitis suppurativa, which causes deep, recurring lumps and tunnels under the skin, primarily in areas like the armpits and groin. This condition is known to be highly inflammatory, and doctors have long suspected that it frequently leads to anemia. However, the exact chain of events linking the skin inflammation to the drop in red blood cells was not fully quantified. Researchers wanted to understand the specific mechanism at play: does the inflammation directly stop red blood cell production, or does it work through an intermediate step? Specifically, they investigated a hormone called hepcidin, which acts as the body's master regulator for iron. Hepcidin controls how much iron is absorbed from food and how much is released from storage. The central question was whether the inflammation triggers hepcidin to rise, and if that rise in hepcidin is what actually causes the anemia.

To answer this, the researchers analyzed data from 88 adults who had been diagnosed with hidradenitis suppurativa. They looked at blood samples to measure the levels of CRP, hepcidin, and hemoglobin, which is the protein in red blood cells that carries oxygen. They found that more than half of the patients in the group were anemic. When they compared the blood test results, a clear pattern emerged. Patients with higher levels of inflammation, indicated by higher CRP, also had higher levels of hepcidin. At the same time, these same patients had lower levels of hemoglobin. This suggested a chain reaction: the inflammation was driving up hepcidin, which in turn was driving down hemoglobin.

The researchers then used a statistical method to test if hepcidin was the true cause of the link between inflammation and anemia. They found that the connection between inflammation and low hemoglobin was substantially explained by the rise in hepcidin. In fact, the study calculated that hepcidin was responsible for about two-thirds (66.8%) of the effect that inflammation had on lowering hemoglobin levels. When the researchers accounted for hepcidin in their models, the direct link between inflammation and anemia became non-significant, meaning that after considering the role of hepcidin, the inflammation alone did not show a statistically significant independent effect on lowering hemoglobin in this group. This provided strong statistical evidence that the body's iron-regulating hormone is the primary bridge connecting the skin disease to the blood disorder.

The study also observed a dose-response relationship, meaning that as the level of inflammation increased, the severity of the anemia worsened. Patients with the highest levels of CRP had the lowest hemoglobin and the highest levels of hepcidin. This gradient effect reinforced the idea that the more severe the inflammation, the more the body locks away its iron, making it unavailable for making new red blood cells. The researchers noted that this mechanism is consistent with what is known about anemia of chronic disease in other conditions, but this was the first time the specific contribution of hepcidin had been measured and quantified in hidradenitis suppurativa.

These findings have important implications for how doctors might treat anemia in patients with this skin condition. Since the study identified hepcidin as the key mediator, it suggests that simply giving iron supplements might not work if the body is still being told to lock the iron away by high levels of hepcidin. Instead, the results support the idea that treating the underlying inflammation is crucial. If the inflammation is reduced, hepcidin levels should drop, allowing the body to access its iron stores and build new red blood cells naturally. The researchers concluded that managing the systemic inflammation is not just about clearing the skin lesions but is also an essential part of preventing the fatigue and weakness caused by anemia in these patients. While the study was limited by its size and the fact that it looked at a single point in time rather than following patients over years, the statistical evidence for the role of hepcidin was robust, offering a clear path forward for future treatments and research.