STEPTRACKERGENERAL PRINCIPLES | PATHOLOGY + IMMUNOLOGY | HIGH-YIELD REVIEW

Systemic Signs & Acute-Phase Reactants

How a local fight becomes a whole-body response: fever, leukocytosis, liver proteins, and a fast ESR.

FOCUS ON
IL-1, TNF and IL-6 leave the tissue and act at a distance. In the hypothalamus they cause fever (via PGE₂). In the liver they make acute-phase proteins, including hepcidin, which causes anemia of chronic disease. In the marrow they cause leukocytosis. Know which proteins rise and which fall.
SIGNAL / MARKER
SOURCE · TRIGGER
EFFECT
CLINICAL LINK
IL-1 & TNF
endogenous pyrogens
Activated macrophages.
Hypothalamic COX-2 → PGE₂ → higher set point → fever; endothelial activation
NSAIDs and acetaminophen lower fever by blocking PGE₂
IL-6
hepatic messenger
Macrophages, T cells, endothelium.
Liver makes acute-phase proteins; contributes to fever
Tocilizumab blocks IL-6 receptor
TNF excess
severe states
Massive macrophage activation.
Vasodilation, capillary leak, DIC; muscle and fat breakdown (cachexia)
Septic shock; cancer cachexia
Leukocytosis
marrow response
IL-1, TNF release marrow pools; immature bands appear (left shift).
Bacteria → neutrophils · viruses → lymphocytes · parasites/allergy → eosinophils
Left shift = bacterial infection
Positive acute-phase reactants
↑ in inflammation
Liver, under IL-6.
CRP (opsonin), ferritin, fibrinogen, hepcidin, serum amyloid A, haptoglobin, complement, procalcitonin
Hepcidin → anemia of chronic disease; SAA → AA amyloid
Negative acute-phase reactants
↓ in inflammation
Liver shifts production away.
Albumin, transferrin, transthyretin (prealbumin)
Low albumin in sick patients is not only nutrition
ESR
indirect, slow
Fibrinogen coats RBCs → stacks (rouleaux) → faster settling.
↑ infection, autoimmunity, malignancy, pregnancy, anemia · ↓ sickle cell, polycythemia, heart failure
Very high in multiple myeloma and giant cell arteritis
CRP
direct, fast
Liver, within hours; falls quickly as inflammation settles.
Binds microbes → activates complement, opsonizes
Tracks response to therapy better than ESR

Mechanism — one cytokine burst, four organs

Infection / injuryMacrophages activated
→
IL-1 · TNF · IL-6Into the blood
→
HypothalamusPGE₂ → fever
LiverCRP, ferritin, fibrinogen, hepcidin
MarrowNeutrophilia, bands
Muscle & fatCachexia (TNF)
VesselsLeak, shock, DIC

Reading the white count

PATTERN
THINK
Neutrophilia + bands
Bacterial infection; also steroids (demargination, no bands)
Lymphocytosis
Viral infection; pertussis (toxin blocks exit from blood); CLL
Eosinophilia
Helminths, allergy/asthma, drugs, Addison, Hodgkin
Monocytosis
Chronic infection (TB), recovery phase
Basophilia
Myeloproliferative neoplasm, especially CML

How it's tested

COMMON CONFUSIONFerritin is an acute-phase reactant. Inflammation raises it even when iron stores are low, which can hide coexisting iron deficiency.
THE TRAP"Low serum iron, low TIBC, high ferritin" in a patient with RA is anemia of chronic disease. IL-6 raises hepcidin, which traps iron in macrophages.
YOUR APPROACHSort cytokine targets by organ: brain → fever, liver → acute-phase proteins, marrow → leukocytosis. Then check whether the marker is direct (CRP) or indirect (ESR).

If you see… think…

Fever pathway → IL-1/TNF → hypothalamic COX-2 → PGE₂
RA patient: low iron, low TIBC, high ferritin → hepcidin (anemia of chronic disease)
Cancer patient wasting despite eating → TNF-driven cachexia
Elevated WBC with many bands → bacterial infection (left shift)
Elderly patient with very high ESR, anemia, bone pain → multiple myeloma (rouleaux)
Near-zero ESR in a sickle cell patient → abnormal RBC shape prevents rouleaux
Sepsis with hypotension and capillary leak → TNF and IL-1
Hospitalized inflamed patient, low albumin and prealbumin → negative acute-phase reactants
Pertussis with marked lymphocytosis → toxin blocks lymphocyte exit