Acute Phase Proteins
o Acute-phase proteins (APPs) are a class of proteins whose concentrations in
blood plasma either increase (positive acute-phase proteins) or decrease
(negative acute- phase proteins) in response to inflammation.
o This response is called the acute-phase reaction (also called acute-phase
response).
o The acute-phase reaction characteristically involves fever, acceleration of
peripheral leukocytes, circulating neutrophils and their precursors.
o In response to injury, local inflammatory cells (neutrophil and macrophages)
secrete a number of cytokines into the bloodstream, most notable of which are
the interleukins IL1, and IL6, and Tumor necrosis factor a( TNF-a).
o The liver responds by producing many acute-phase reactants.
o At the same time, the production of a number of other proteins is reduced; these
proteins are, therefore, referred to as "negative" acute-phase reactants.
o These are also important mediators produced in the liver during acute and
chronic inflammatory states.
o Interleukin-6 (IL-6) is the primary cytokine responsible for inducing the
production in the liver.
o IL-1, tumor necrosis factor-alpha (TNF-a), and interferon-gamma (IFN-y)
can also induce the production of acute-phase reactants.
o Acute phase reactant proteins are non-specific markers of inflammation, and the
tests used should be interpreted in conjunction with history, physical
examination, and other laboratory tests and imaging.
o Their levels will be elevated during both acute and chronic inflammation.
o However, the highest levels are attained in acute inflammation during an acute
infection or after trauma.
o Acute-phase proteins are part of the innate immune response and its
biological function, generally relate to defense to pathological damage and
restoration of homeostasis.
o However, a specific acute phase proteins may have both pro- and anti-
inflammatory effects.
Positive phase reactant:
1- ESR 2- C-reactive Protein (CRP)
3- Ferritin 4- Haptoglobin
5- Fibrinogen 6- C3 & C4
7- Serum Amyloid A 8- Alpha-1antitrypsin
Negative phase reactants:
1- Albumin 2- Transferrin
3- Transthyretin 4- Retinol binding protein
Positive acute phase proteins
o Positive acute-phase proteins increase in plasma concentration in response to
inflammation (usually within 1-2 days).
o Positive APPs are further categorized as major, moderate or minor, depending
on the degree of increase.
o Major APP: A protein with a low concentration in the serum will increase over
100 — 1000-fold, reaching a peak 24-48 hours after trauma , then rapidly
decreasing.
An example of a major APP is Serum amyloid A.
o Moderate APP: Present in the blood but increases 5 — 10-fold upon
stimulation, peaking around 48 — 72 hours after trauma, then decreases at a
slower rate than major APPs.
o Minor APP: Increase only by 50 - 100% above resting levels and at a gradual
rate.
C-reactive Protein (CRP)
o The name CRP arose because it was first identified as a substance in the serum
of patients with acute inflammation that reacted with the "c" carbohydrate
antigen of the capsule of pneumococcus.
o C-reactive protein is a positive direct inflammatory marker.
o In inflammation, cytokines induce hepatocytes to produce CRP, which itself
promotes recognition and elimination of harmful stimuli.
o CRP begins to rise within 4-6 hours after the onset of inflammation and peaks
within 36-50 hours.
o CRP has a half-life of 4-7 hours: therefore, serum levels are a measure of active
inflammation .
o Because CRP rises quickly and has a short half-life, it can be a useful measure
for diagnosis and response to treatment .
o An elevated CRP level indicates some level of active inflammation, but that in
itself is not entirely helpful.
o Many things that cause cellular stress (obesity, smoking, diabetes, hypertension,
fatigue, depression, advanced age, and many others) cause some elevation in CRP
concentration.
o However, 88-94% of patients with a markedly elevated CRP concentration (> 500
mg/L) have a source of bacterial infection .
o Because CRP is produced in the liver, falsely low CRP levels can be seen in
patients with hepatic failure
o CRP is a marker of bacterial inflammation and has a higher sensitivity than
ESR, and is a direct measure of the inflammatory response.
o The normal range for CRP is between 2 to 10 mg/L.
o Levels of CRP can increase 100- to 1000-fold during acute inflammation.
o The main functions of CRP are to help promote phagocytosis and the innate
immune response against foreign infectious pathogens.
Haptoglobin
o Haptoglobin is a protein made by the liver. It attaches to hemoglobin.
o Most hemoglobin is located inside red blood cells, but small amounts circulate in
the bloodstream
o Haptoglobin has bacteriostatic effect
o It will be elevated in many inflammatory diseases, such as ulcerative colitis, acute
rheumatic disease, heart attack, and severe infection.
Procalcitonin
o Is a biomarker that is released in response to bacterial infections and can be used
to differentiate the etiology of infectious processes.
o Under normal conditions, procalcitonin is produced by the parafollicular (C cells)
of the thyroid gland. It is then converted to calcitonin and released from C cells.
o However, during inflammation, lipopolysaccharide, microbial toxins, or
inflammatory mediators can activate the procalcitonin gene in other tissues,
including the liver, kidney, adipocytes, pancreas, colon, and brain.
o Procalcitonin is a sensitive marker for following the progression of infections,
especially for pneumonia and sepsis.
o Levels of procalcitonin can be used to guide antibiotic therapy.
o Is a biomarker that is released in response to bacterial infections and can be used
to differentiate the etiology of infectious processes.
o Under normal conditions, procalcitonin is produced by the parafollicular (C cells)
of the thyroid gland. It is then converted to calcitonin and released from C cells.
o However, during inflammation, lipopolysaccharide, microbial toxins, or
inflammatory mediators can activate the procalcitonin gene in other tissues,
including the liver, kidney, adipocytes, pancreas, colon, and brain.
o Procalcitonin is a sensitive marker for following the progression of infections,
especially for pneumonia and sepsis.
o Levels of procalcitonin can be used to guide antibiotic therapy.
o Procalcitonin is downregulated during viral infections.
o Procalcitonin levels become detectable in patient's serum as early as 3-6 hours
after onset of inflammation and remain elevated for 12-36 hours after resolution.
o Concentrations of procalcitonin increase in response to bacteria and decrease in
response to viruses.
o Procalcitonin is a sensitive marker for sepsis and can be used to guide treatment.
o Procalcitonin has replaced CRP as a diagnostic parameter in sepsis because PCT
has higher sensitivity than CRP in sepsis.
o CRP is no longer used as a diagnostic parameter in sepsis, but it can be useful in
the follow-up
Ferritin
o Ferritin is a blood protein that contains iron. A ferritin test helps your doctor
serum iron understand how much iron your body stores. If a ferritin test reveals
that your blood ferritin level is lower than normal, it indicates your body's iron
stores are low and you have iron deficiency.
o The role of ferritin is to sequesters iron to inhibit microbial iron scavenging.
o During malignancy and infection, ferritin
concentrations are elevated to reduce free iron
available to tumor cells or pathogens, respectively.
o Itis upregulated by proinflammatory cytokines.
Fibrinogen
o Fibrinogen is a protein that helps with blood clotting.
o The role of fibrinogen as a coagulation factor is to promote endothelial repair.
o Fibrinogen correlates with ESR.
Erythrocyte Sedimentation Rate (ESR)
o Erythrocyte sedimentation rate is an indirect measure of acute phase reactants
and is also a positive inflammatory marker.
o ESR is very simply the rate at which red blood cells settle in a vertical tube,
measured in mm/h.
o The rate of RBC sedimentation is affected by the components of the patient's
serum.
o The main acute phase reactant that causes an increased ESR is fibrinogen, but
concentrations of other proteins such as immunoglobulins also contribute.
o Increased fibrinogen and other proteins cause RBCs to aggregate and settle
faster.
o ESR typically begins to increase within 24 hours after the onset of trauma.
o Because the half-life of fibrinogen is about 100 hours and that of IgG is more than
a week, ESR can remain elevated for weeks after the initial rise .
o ESR can be a useful tool to aid in the diagnosis and management of certain
specific situations, but like CRP it lacks specificity.
o Marked ESR increases (>100 mm/hr.) are associated most often with infection
(33%) and neoplasm (17%), however end stage renal disease is also a
significant cause (17%) .
o The normal ESR value for men is 0 to 20 mm/hour and for women 0 to 30
mm/hour.
o Factors that increase ESR include infection, inflammation, malignancy,
pregnancy, autoimmune diseases (SLE, RA, thyroiditis), multiple myeloma,
anemia, macrocytosis, and old age.
o Factors that decrease ESR include hypogammaglobulinemia,
hypofibrinogenemia, microcytosis, spherocytosis, sickle cell disease,
polycythemia, and extreme leukocytosis (e.g., chronic lymphocytic leukemia).
Negative acute phase proteins
o Negative acute phase proteins decrease in plasma concentration by greater than
25% in response to inflammation.
o This reduction can occur rapidly (within 24 hours) or may decrease gradually
over a period of days.
o The two main negative acute phase proteins are albumin and transferrin.
o The mechanism by which their concentrations decrease is likely multifactorial,
including decreased production by the liver in response to inflammatory
cytokines, and possibly increased loss or increased proteolysis.
Transferrin
o Transferrin is a blood plasma glycoprotein that plays a central role in iron
metabolism and is responsible for ferric-ion delivery.
o Transferrin functions as the most critical ferric pool in the body.
o It transports iron through the blood to various tissues, such as the liver, spleen,
and bone marrow.
o Macrophages internalize transferrin to sequester iron and inhibit microbial iron
scavenging.
o Usually measured to assess iron status.
Albumin
o Albumin is a protein made by your liver.
o Albumin enters the bloodstream and helps keep fluid from leaking out of the
blood vessels into other tissues.
o it is also carrying hormones, vitamins, and enzymes throughout the body.
o Albumin is a negative APP, and its production is decreased to conserve amino
acids for positive APPs
o Reduced production of albumin allows greater increase in the amount of amino
acids available for positive APP production.
o Albumin concentration falls gradually and reduction in concentration is more
noticeable in chronic inflammatory disease.
o CRP is a highly sensitive marker for detecting inflammation.
o It is not specific to any disease or organ.
o In patients with systemic lupus erythematosus (SLE), CRP is often within normal
limits, and ESR is generally elevated.
o In SLE patients with elevated high-sensitivity CRP ,an infection should be ruled
out because elevated CRP is a predictor for active infection with high specificity
in patients with SLE
o Haptoglobin levels increase during inflammation and decrease during hemolysis.
In patients with hemolysis and inflammation, levels can appear normal.
o Ferritin levels are increased in inflammatory conditions, and levels of transferrin,
a negative APP that transports iron, decrease.
o Ferritin sequesters iron. Prolonged inflammation or malignancy can lead to
anemia of chronic disease.
o Ferritin, transferrin, and serum iron are part of the iron panel laboratory studies.
o Procalcitonin PCT levels can be used to guide treatment in patients with
pneumonia.
o PCT levels greater than 0.25 mcg/L correlate with bacterial infections of the
lower respiratory tract.
o After 2 or 3 days of treatment, lower PCT levels can facilitate the decision to
discontinue pneumonia antibiotic treatment.
o PCT levels greater than 0.5 ng/mL can confirm sepsis.
o PCT should not be used for the diagnosis of pneumonia or for deciding if the
antibiotics are necessary to treat pneumonia.
o It should only be as a guide antibiotic treatment.
