Inflammatory anemia reviewed in the New England Journal of Medicine

Inflammatory anemia (also known as chronic disease anemia) and iron deficiency anemia are the two most common anemias
.
Inflammatory anemia was initially thought to be primarily associated
with infectious, inflammatory, or neoplastic diseases.
Inflammatory anemia is now recognized as a major cause or predisposition for anemia in many other patients with systemic inflammation, including chronic kidney disease, chronic heart failure, chronic obstructive pulmonary disease, or cystic fibrosis
.

The New England Journal of Medicine (NEJM) has published a review detailing the pathogenesis, diagnosis, and treatment of
inflammatory anemia.
We will introduce its main contents
here.

Iron metabolism

In people with normal erythropoiesis, when there is no inflammation and the amount of iron eaten is normal, systemic iron balance can maintain plasma iron levels between 10 and 30 μM, and systemic iron stores are between 0.
3 and 1 g, of which iron levels in women of childbearing age are low, mostly at the lower limit
of the normal range.
The interaction between the iron-regulating hormone hepcidin (hepcidin) and membrane ferroportin (ferroportin) produced by hepatocytes is the main mechanism for maintaining iron homeostasis; The latter is both a hephotrin receptor and the only cellular iron output channel through which iron is transferred into plasma (Figure 1
).
Heptidronin inhibits the iron output activity of membrane iron transporters, thereby controlling the transfer of iron from duodenal cells (which absorb iron), macrophages (reclaim iron from senescent red blood cells), and hepatocytes (stored iron) into plasma
.

Figure 1.
Changes in iron homeostasis in inflammatory anemia

The iron in the plasma binds to transferrin and is mainly delivered to nucleated red blood cells
in the bone marrow.
These red blood cells consume iron to synthesize heme and hemoglobin, and a small portion of iron is used to meet the iron needs
of all other organs and tissues.
Baseline hephotrin synthesis is controlled
by iron storage and feedback from plasma iron levels.

The iron regulatory system in the liver is based on the complex interactions between at least two iron receptors in the liver that interact with the bone morphogenetic protein receptors of liver cells, affecting the signaling pathways
that transcriptionally regulate hephotrene synthesis.
These two types of ferroreceptors perceive levels of divalent transferrin in plasma (transferrin receptors 1 and 2) and the amount of iron stored in the liver (receptors have not been identified),
respectively.
When iron is abundant, these iron sensing mechanisms increase the synthesis of hephotronin and reduce the synthesis of hepcidin in the event of iron deficiency, thereby regulating iron absorption and release in response to different iron levels
in the body.
Inflammation significantly improves hepcidin synthesis, which is extremely important
in the pathogenesis of inflammatory anemia.
Inflammation mainly stimulates the JAK2-STAT3 pathway through interleukin-6, thereby enhancing the transcription of the hepcidin gene in hepatocytes and increasing
hepcidin synthesis.
In a state of relatively low degree of systemic inflammation (eg, obesity), there will be a small but clinically significant increase in serum hepcidine; However, in the serum of patients with sepsis, heptin levels may be more than
twice as high as in normal people.

Erythrocytogenesis

Red blood cells are derived from hematopoietic stem cells in the bone marrow and gradually develop into red blood cell lines, while their proliferative ability gradually weakens
.
Although the specific mechanisms that control the direction of hematopoietic stem cell differentiation are not fully understood, some progenitor cells have the potential to differentiate into myeloid, erythrocyte, or megakaryocyte lines, and their pathway selection depends on the interaction
between two opposing transcription factors.
PU.
1 is beneficial for myeloid differentiation, while GATA1 is beneficial for erythrocyte line differentiation
.
The relative proportions of these two transcription factors can be affected by inflammation
.

The first precursor cells that fully differentiate into red blood cells are BFU-E (Red Burst Colony Formation), which is defined as the ability of these cells to proliferate and generate large numbers of red blood cell colonies
when cultured in semi-solid media containing appropriate growth factors.
The cell type after further differentiation is CFU-E (Red Colony Forming Cell) with fewer
RBCs produced under the corresponding conditions.
CFU-E further differentiates into protoerythrocytes
.
Each protoerythrocyte undergoes four or five more divisions, each producing gradually maturing red blood cells that can synthesize hemoglobin, and finally the nucleus disappears, producing reticulocytes
.
Reticulocytes mature in the blood into biconcave red blood cells
.
The survival of CFU-Es and early erythrocytes is determined by erythropoietin, and the differentiation and division of erythrocytes is controlled
by the levels of erythropoietin and iron, as well as one or more activated protein-like members of the TGF-β superfamily.
Red blood cell production depends on the level of divalent transferrin in the blood plasma, which is associated
with iron-restricted anemia.

pathogenesis

Evolutionary perspective

The body's response to infection or injury, with the host's defense mechanisms superior to homeostatic processes such as erythropoiesis, is a beneficial response; This mechanism helps us understand inflammatory anemia
.
At the expense of red blood cell production and survival, it leads to hypoironemia and increased leukocyte production and activation, thus serving host defenses
.
Increased leukogenesis and hypoferritemia lead to a decrease in the number of red blood cell precursors, while macrophage activation leads to a shortened red blood cell lifespan (Figure 2
).
Long RBC lifespans buffer the consequences
of erythrocytopenia during most acute infections.
In chronic infectious or inflammatory diseases, the number of red blood cells often decreases to a stable anemia state, where red blood cell destruction matches erythrocytopenia
.

Figure 2.
Role of systemic inflammatory response in the development of anemia

Hypochyteremia

Hypoferritemia occurs
within a few hours after the onset of an infection or other inflammatory event.
A decrease in iron content and transferrin saturation in plasma may help prevent the production
of non-transferrin-binding iron.
Plasma and other extracellular fluids contain only 2 to 3 mg of iron, iron levels change every few hours, and when iron supply or demand changes, the iron content in plasma may be unstable
.
Red blood cell production is the main consumable of iron in plasma, while macrophages (phagocytosis of senescent or damaged red blood cells) are the main source
of iron in plasma.
Both are strongly influenced by various inflammatory processes, so strict control of iron levels during inflammation is especially important
for the host's defenses.
Stimulated by interleukin-6, high levels of circulating hepcillin inhibits the release of intracellular iron into plasma and reduces the absorption of iron by the intestine and the release of iron by macrophages in the
spleen and liver.
Macrophages and hepatocytes secrete large amounts of ferritin
through non-classical mechanisms.
Hypoferritemia associated with elevated plasma ferritin and ferritin levels is characteristic of inflammatory anemia, while iron deficiency anemia is characterized by hypoferritemia associated with decreased plasma ferritin and ferritin
levels.

Inflammatory hypoferritemia, like systemic iron deficiency due to hypoferremia, inhibits red blood cell production
.
Iron is not a simple random restriction
on the synthesis of hemoglobin.
In contrast, hypoferritemia inhibits erythropoiesis at a relatively high set point (transferrin saturation of 15% to 20%), which appears to be intended to protect the iron supply to other tissues (such as muscles, central nervous systems, and non-red bone marrow) that are less
affected by decreased plasma iron levels.

Bone marrow reprogramming

Leukocytosis and leukocytosis in the bone marrow are early reactions to inflammation manifested by an increase in the number of myeloid precursor cells (the ratio of myeloid to red precursor cells >4:1).

The mechanism of bone marrow reprogramming involves the activation of the transcription factor PU.
1 by inflammatory cytokines such as TNF-α and interferon-γ, thereby promoting myeloid cell and lymphocyte production, while erythropoiesis is suppressed
.
Inflammatory cytokines also inhibit BFU-E's ability to
promote the maturation of red blood cells.

Inflammation also inhibits the action of
erythropoietin.
Some patients with systemic inflammation have decreased
levels of erythropoietin in their bodies.
The ability of erythrocyte precursor cells to respond to erythropoietin is also affected by inflammation; For example, patients with inflammatory end-stage renal disease have an increased
need for exogenous erythropoietin.
Part of the cause of erythropoietin resistance is associated with a decrease in the number of erythropoietin receptors on erythropoietin progenitor cells, resulting in a decrease in
the ability of these cells to proliferate.

Red blood cell lifespan is shortened

In patients with inflammatory anemia, the lifespan of red blood cells is shortened by about 25%, about 90 days
.
Shortened red blood cell lifespan is also observed in many inflammatory patients without anemia, so anemia occurs only when the compensatory function of red blood
cells is impaired.
In inflammatory anemia, there are many causes of increased red blood cell destruction, including macrophage activation (which may affect the threshold for recognizing red blood cell aging) and bystander inflammatory damage
of red blood cells.
The term "inflammatory anemia" refers to a disease
in which the hemophagocytic action of activated macrophages is the main cause of anemia.
Inferred from hemolytic anemia associated with infection and severe systemic inflammation, red blood cells may even be damaged
in inflammatory anemia by the deposition of antibodies and complement and damage to the microvascular fibrin chain.

Diagnosis of inflammatory anemia

Symptoms in patients with mild to moderate inflammatory anemia include fatigue, poor exercise tolerance, and dyspnea, but these symptoms are difficult to distinguish from
the effects of chronic systemic inflammation.
Inflammatory anemia can be diagnosed when patients with n-cell-positive pigmented anemia have evidence of systemic inflammation (elevated erythrocyte sedimentation rate or C-reactive protein levels) and evidence of iron restriction due to nonsystemic iron deficiency (decreased transferrin saturation [<20%], and high serum ferritin levels [>100 micrograms/L]
).

The main difficulty in diagnosing the diagnosis is the coexistence of true iron deficiency and inflammatory anemia (especially blood loss due to underlying disease), or iron deficiency
due to malnutrition, chronic inflammation, or increased iron demand (in children or pregnant women).

There are several biomarkers used to distinguish inflammatory anemia from true iron deficiency
.
In fact, when inflammatory anemia is complicated by iron deficiency, these markers are of little
significance.
Negative iron staining in bone marrow specimens was used as a diagnostic criterion for iron deficiency, but it is no longer applicable
.

A practical clinical approach to this challenge is to focus on detecting and diagnosing all diagnostic procedures and iatrogenic blood loss due to all types of occult blood loss, most commonly gastrointestinal blood
loss.
Oral or intravenous iron may also be considered for therapeutic trials
.
Of course, the urgency of iron supplementation, adverse reactions, and the impact
of iron supplementation on underlying disease and systemic health need to be considered.

Systemic inflammation affects the absorption of oral iron; But in patients with mild inflammation, this effect is counteracted
by the absorption-promoting effect of iron deficiency.
Thus, in inflammatory anemia, oral iron is not as reliable as the parenteral pathway, and the rate of correction of iron deficiency is slower
.
In contrast, intravenous iron is safer and very effective
for inflammatory anemia with iron deficiency.
If the anemia is caused only by iron deficiency, then estimate the amount of iron needed to completely correct the anemia and inject half
of that dose.
Hemoglobin rises within 4 weeks after intravenous iron therapy and stabilizes within 8 weeks, but patients may feel improvement
in symptoms earlier.

Animal models and clinical data suggest that iron excess in the form of non-transferrin-binding iron enhances microbial pathogenicity
.
Indiscriminate iron supplementation may increase morbidity and mortality
.

treat

Treatment of infectious or inflammatory diseases that cause inflammatory anemia can improve not only anemia, but also a variety of symptoms and defects
caused by the primary disease.
Therefore, this treatment makes more sense than treatment for inflammatory anemia alone
.
Anemia can be quickly corrected by treating the underlying disease: such as anti-interleukin-6 antibody for Castleman's disease, glucocorticoids for giant cell arteritis, and anti-interleukin-6 or anti-TNF-α antibodies for rheumatoid arthritis, and hemoglobin can be significantly elevated
after 2 weeks of treatment.
In patients with tuberculosis with anemia, about one third of patients have complete remission of anemia after 1 month of antimicrobial therapy, and about half of patients have anaemia remission
after 2 months of treatment.

Unfortunately, the underlying inflammation in some patients is difficult to treat
effectively.
It has been found that erythropoietin derivatives with or without intravenous iron are available as a specific treatment regimen for inflammatory anemia, which has been studied
mainly in patients with chronic kidney disease.
There are few current clinical studies on the mechanism of action of erythropoietin derivatives combined with intravenous iron, but it is speculated that combination drugs are expected to counteract the restrictive effects of inflammation on iron and the associated resistance
to endogenous erythropoietin.

A systematic review of the use of erythropoietin derivatives for the treatment of anemia in patients with chronic kidney disease who did not require renal replacement therapy showed a marked improvement in hemoglobin levels and some improvement in
anemia-related symptoms.
However, in patients requiring renal replacement therapy, the risk of disease progression did not change
.
The researchers analyzed the risks and potential benefits of darbopoetin treatment in patients with chronic kidney disease with relatively mild anemia (mainly treatment-related stroke), and the authors suggest that darbopoetin
should not be used in such patients with mild anemia.
However, for severe anemia (hemoglobin < 10 g/dL), treatment with darbopoetin may be required
.
Research on these treatments in patients with inflammatory anemia without chronic kidney disease is very limited, and the specific risks and benefits of erythropoietin therapy remain uncertain
.

New drugs specifically for the treatment of inflammatory anemia are under development
.
The use of hephotrin conjugates to reduce heptitemperin levels, or to block hephotrin binding to membrane iron transporters, or to antagonize the signaling pathway that stimulates heptitemperin synthesis during inflammation, thereby reversing hypoferremia in inflammatory anemia
.
Prolineyl hydroxylase inhibitors stimulate the production of erythropoietin and may also act directly on the intestinal mucosa, promoting iron absorption, thereby improving iron restriction
.

Conclusion

Inflammatory anemia is a syndrome associated with systemic inflammation with a high
prevalence.
Inflammatory anemia is easily diagnosed as n-cell nextrochrome anemia, and patients have low transferrin saturation but high
serum ferritin levels.
Treatment of the underlying disorder significantly improves anemia
.
Further understanding of the pathogenesis of inflammatory anemia promotes the continuous development of targeted therapeutic drugs, which is expected to provide more treatment options
in the future.


Reference 1.
Ganz T.
Anemia of inflammation.
N Engl J Med 2019; 381:1148-57.

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