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Physiology, Acute Phase Reactants

Authors

Radhika Gulhar1; Muhammad A. Ashraf2; Ishwarlal Jialal3.

Affiliations
1 California Northstate Univeristy College of Medicine
2 University of New England School of Osteopathic Medicine
3 VA MEDICAL CENTER, MATHER , CA

Last Update: May 4, 2020.

Introduction
Acute phase reactants (APR) are inflammation markers that exhibit significant changes in serum
concentration during inflammation. These are also important mediators produced in the liver
during acute and chronic inflammatory states. Interleukin-6 (IL-6) is the primary cytokine
responsible for inducing the production in the liver. IL-1, tumor necrosis factor-alpha (TNF-alpha),
and interferon-gamma (IFN-gamma) can also induce the production of acute-phase reactants. Acute
phase reactants cause several adverse effects. These include fever, anemia of chronic disease,
anorexia, somnolence, lethargy, amyloidosis, and cachexia (fat and muscle loss, anorexia,
weakness).

Acute phase reactants can be classified as positive or negative, depending on their serum
concentrations during inflammation. Positive acute phase reactants are upregulated, and their
concentrations increase during inflammation. Negative acute phase reactants are downregulated,
and their concentrations decrease during inflammation. Positive acute phase reactants include
procalcitonin, C-reactive protein, ferritin, fibrinogen, hepcidin, and serum amyloid A. Negative
acute phase reactants include albumin, prealbumin, transferrin, retinol-binding protein, and
antithrombin. [1]

Cellular
Macrophages sense bacterial products through Toll-like receptors (TLR) and regulate the
inflammatory response. TLR4 senses the gram-negative bacterial lipopolysaccharide (LPS).
Downstream signaling leads to the activation of the transcription factor, nuclear factor kappa beta
(NF-kB), and increased production of IL-6. IL-6 activates liver production of other acute-phase
proteins. Tissue injury and trauma can also activate the acute-phase reaction (APR). The purpose of
acute-phase proteins released during APR is to participate in blood coagulation, defense against
infection, transport metabolites, nutrients and hormones, and maintenance of homeostasis. IL-6,
IL-1beta, TNF-alpha, glucocorticoids, and growth factors are the primary mediators of acute-phase
proteins (APP) gene expression.[2][3]

APPs are divided into positive and negative APPs. The concentrations of positive APPs increase
during inflammation, and the concentration of negative APPs decrease. Positive APPs include C-
reactive protein, haptoglobin, angiotensinogen, alpha1-acid glycoprotein, serum amyloid A,
lipopolysaccharide-binding protein (LBP), ferritin, alpha1-antitrypsin, hepcidin, fibrinogen, serum
amyloid A, vitronectin, procalcitonin, among others. Negative APPs include albumin, transthyretin
(prealbumin), antithrombin, and transferrin.
Erythrocyte sedimentation rate (ESR): ESR is the measurement of the distance that red blood
cells in the anticoagulated blood fall in a vertical tube after one hour. Fibrinogen reduces the
charge on the red blood cell surface, which causes them to aggregate rapidly. As a result, ESR
increases. ESR is used to indirectly measure the amount of fibrinogen by determining the rate at
which erythrocytes settle inside a vertical tube in one hour. The ESR level starts to rise within 24 to
48 hours of inflammation. An increase in ESR can be indicative of inflammation.[4]

C-reactive protein: CRP is a marker of bacterial inflammation and has a higher sensitivity than
ESR and is a direct measure of the inflammatory response. It was first discovered by Tillet and
Francis in 1930 when they showed it reacted to the C-polysaccharide of Streptococcus
pneumoniae in patients with pneumococcal pneumonia. It belongs to a highly conserved family of
proteins referred to as pentraxins, which are typified by five protomers around a central pore, and
its half-life does not change between health and disease, making the production rate the sole
determinant of plasma concentrations.[2][3] The normal range for CRP is between 2 to 10 mg/L. The
CRP levels start to rise after 4 to 6 hours and peaks by 36 to 50 hours. Levels of CRP can increase
100- to 1000-fold during acute inflammation. The main functions of CRP are to help promote
phagocytosis and the innate immune response against foreign infectious pathogens.[4]

Procalcitonin: PCT is a 14.5 kDa peptide. IL-6, IL-1, and TNF-alpha stimulate its secretion. However,
it appears that secretion is not activated by IFN-gamma (produced mainly in response to viral
infections), making it a sensitive marker of bacterial infections.[5] 

Function
Procalcitonin: 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. However, during
inflammation, LPS, microbial toxins, or inflammatory mediators, can activate the procalcitonin
gene in other tissues, including liver, kidney, adipocytes, pancreas, colon, and brain. Unlike the
procalcitonin produced by the thyroid gland, procalcitonin produced in response to inflammation
is directly released into blood circulation. Procalcitonin is a sensitive marker for following the
progression of infections, especially for pneumonia and sepsis. Levels of procalcitonin can be used
to guide antibiotic therapy.

C-reactive protein: CRP binds to several pathogens acting as an opsonin. It can also bind to
degenerating cells and cell remnants. CRP also activates complement by the classical C1q pathway.
CRP is used as a clinical measurement of ongoing inflammation.[3]

Serum amyloid A: The role of SAA is to function as an inhibitor of many biological processes,
including fever, platelet activation, mobilization of monocytes, and chemotactic effect on various
immune cells. In tissues, SAA attracts and modulates inflammatory cells and inhibits respiratory
burst. As an APP, SAA influence HDL cholesterol transport. SAA can bind to the LPS comparable to
LPS binding protein (LBP). The prolonged elevation of SAA can lead to secondary amyloidosis. [6]

Hepcidin: Hepcidin inhibits iron absorption in the intestinal mucosal cells by binding to the
ferroportin and inhibits iron transport by binding to ferroportin in macrophages. Increased
hepcidin during inflammation causes anemia of chronic disease. [2][3]

Haptoglobin: Intravascular hemolysis releases free hemoglobin in the circulation. Free

hemoglobin is an oxidizing agent and can cause tissue damage. Bacteria can utilize heme for the
iron requirement. Haptoglobin is a scavenger protein that has antioxidant, antimicrobial, and anti-
inflammatory properties. It is antioxidant because it removes free hemoglobin from the blood, and
it is antimicrobial because it reduces iron availability to the pathogens. Its anti-inflammatory
properties are due to its binding to CD11b/CD18 integrins on neutrophils.[7] Because haptoglobin
binds to hemoglobin, levels of haptoglobin decrease during intravascular hemolysis. As a positive
APP, its levels increase during inflammation. Therefore, haptoglobin levels can appear within
normal limits in patients with intravascular hemolysis and inflammation.

Ferritin: The role of ferritin is to sequesters iron to inhibit microbial iron scavenging. During
malignancy and infection, ferritin concentrations are elevated to reduce free iron available to
tumor cells or pathogens, respectively. It is upregulated by proinflammatory cytokines. Some
organisms like pseudomonas cause ferritin levels to drop because they have virulence factor
siderophores (pyoverdine and pyocyanin) that chelate and import iron.

Fibrinogen: The role of fibrinogen as a coagulation factor is to promote endothelial repair.

Fibrinogen also has a C3 complement function. Fibrinogen correlates with ESR.

Alpha-1 antitrypsin (AAT): AAT is a serine protease inhibitor (serpin) that breaks down neutrophil
elastase. It protects the cells against neutrophil elastase activity. AAT deficiency can cause hepatitis,
liver cirrhosis, and panacinar emphysema.

Others: Ceruloplasmin (Cp) contains copper, and it has histaminase-and ferroxidase-activity. Cp

also scavenges Fe2+ and free radicals. Alpha2-macroglobulin (a2MG) binds to the proteolytic
enzymes. Alpha1-glycoprotein (a1AGP) influences T-cell function and binds to the steroids such as
progesterone. Alpha1-antichymotrypsins inhibit leukocytes and lysosomal proteolytic enzymes.

Transferrin: Transferrin is a negative APP. Macrophages internalize transferrin to sequester iron

and inhibit microbial iron scavenging.

Albumin: Albumin is a negative APP, and its production is decreased to conserve amino acids for
positive APPs. [1]

Related Testing
The best accepted clinical measures of acute inflammation are CRP and ESR. CRP has the advantage
of being more sensitive and easily measured on automated platforms by nephelometry and
turbidimetry in the majority of clinical laboratories and is a direct readout of the APR. ESR is an
indirect measure of APR proteins mainly fibrinogen. Both can provide results within hours.
However, the quantification of some APPs such as alpha-1antitrypsin (AAT), alpha-1-acid
glycoprotein, alpha-2 macroglobulin is not as well validated and standardized as CRP. Fibrinogen
rises much later than CRP and its concentration only increased around two folds.[2] 

Assessing intravascular hemolysis with haptoglobin can be inaccurate without tests such as
bilirubin, lactate dehydrogenase, and hemoglobin. Haptoglobin levels increase during
inflammation and decrease during hemolysis. In patients with hemolysis and inflammation, levels
can appear normal.

Procalcitonin is a sensitive marker for sepsis and can be used to guide treatment. Procalcitonin has
replaced CRP as a diagnostic parameter in sepsis because PCT has higher sensitivity than CRP in
sepsis. CRP is no longer used as a diagnostic parameter in sepsis but it can be used in the follow-up.

Ferritin levels are increased in inflammatory conditions and transferrin, a negative APP that
transports iron, levels are decreased. Ferritin sequesters iron. Prolonged inflammation or
malignancy can lead to anemia of chronic disease. Ferritin, transferrin, and serum iron are part of
the iron panel laboratory studies. Iron deficiency anemia and anemia of chronic disease can both
present as microcytic anemia. They can be distinguished by assessing ferritin and transferrin
levels. Anemia of chronic disease patients will have elevated ferritin and low transferrin. Iron
deficiency anemia patients will have lower ferritin and elevated transferrin. Serum iron will be
low in both patients for different reasons. In iron deficiency, low serum iron could be due to
malnutrition, increased demand, or hemorrhage. In anemia of chronic disease, low serum iron is
from impaired distribution of iron mainly due to hepcidin-mediated reduced absorption from
enterocytes and macrophages.[8]

Pathophysiology
There are some disease states that are causally related to APPs, and some are associated with them.
The central role of fibrin during hemostasis and thrombosis is well known. However, fibrinogen
also increases the risk of bleeding and thrombosis in many pathologies, including inflammation,
infection, neurologic disease, and cancer. CRP can activate complement. In cardiac infarction, CRP
has a key role in some forms of tissue alteration. Elevated levels of CRP are associated with the risk
of atherosclerosis. [9]

The prolonged elevation of serum amyloid A (SAA) can eventually lead to secondary amyloidosis.
Amyloidosis is caused by amyloid fibrils (misfolded SAA) depositing extracellularly in various
organs, including heart, liver, tongue, spleen, hematologic, and spleen. Patients can develop
symptoms of restrictive cardiomyopathy or arrhythmia, macroglossia, hepatomegaly,
splenomegaly, cough, and dyspnea. There is a casual relationship between SAA and amyloid fibrils.
However, the cause of misfolded SAA is not fully understood. Sustained high SAA levels, amyloid
enhancing factor, apolipoprotein-E4, impaired SAA-degrading proteases, and many other factors
have been implicated. Some of the diseased states with a prolonged elevation of SAA include
chronic infection, rheumatoid arthritis, familial Mediterranean fever (FMF), inflammatory bowel
disease, and malignancy. [10]

Alpha-1 antitrypsin (AAT) is released from the liver and acts as a serine protease inhibitor (serpin)
that protects the cells from neutrophil elastase activity. AAT deficiency is caused by a mutation in
the SERPINA1 gene. The mutation is more common in European descendants. The production of
AAT in individuals with the mutation is dependent on the allele type. There are three alleles for the
AAT gene: M, S, and Z with autosomal codominant inheritance. The normal allele for the SERPINA1
gene is M, and AAT production in homozygous (PiMM) individuals is normal. The S mutation causes
a moderate decrease in AAT production, and the Z mutation causes a significant decrease.
Therefore, the severity of the disease is dependent on the genotypic expression. Individuals with
two normal alleles, PiMM (protease inhibitor MM), have 100% expression of normal protein and
have normal levels of AAT. Individuals with PiMS have 80% of normal serum levels of AAT.
Individuals with PiSS, PiMZ, and PiSZ have 40-60% serum levels of AAT. Severe AAT deficiency is in
individuals homozygous of the Z allele (PiZZ). They produce 10% of the normal serum AAT.

AAT gene mutation induces AAT protein conformation change in the structure. It affects the liver
and the lungs. In the liver, AAT accumulates because of impaired secretion. As a result, there is
hepatocyte destruction leading to hepatitis and liver cirrhosis. In the lungs, the absence of AAT
causes uninhibited neutrophil elastase activity. It leads to the destruction of pulmonary
architecture and panacinar emphysema.[1]

Clinical Significance
APPs 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. Their
levels will be elevated during both acute and chronic inflammation. However, highest levels are
attained in acute inflammation during an acute infection or after trauma resulting in CRP of 50 to
100 mg/L and ESR exceeding 50 mm/hour.

The best recent evidence relates to procalcitonin (PCT). PCT levels can be used to guide treatment in
patients with pneumonia. PCT levels greater than 0.25 mcg/L correlate bacterial infections of the
lower respiratory tract. Lower PCT levels after 2-3 days of treatment can facilitate the decision to
discontinue pneumonia antibiotic treatment. PCT levels greater than 0.5 ng/mL can confirm sepsis.
PCT should not be used for the diagnosis of pneumonia or for deciding if the antibiotics are
necessary for the treatment of pneumonia. It should only be as a guide antibiotic treatment. [11]

Normal ESR value for men is 0-15 mm/h, and for women 0-20 mm/h. Factors that increase ESR
include infection, inflammation, malignancy, pregnancy, autoimmune diseases (SLE, RA, GCA,
polymyalgia rheumatic, thyroiditis), multiple myeloma, Waldenstrom macroglobulinemia, anemia,
macrocytosis, and old age. Factors that decrease ESR include hypogammaglobulinemia,
hypofibrinogenemia, microcytosis, spherocytosis, sickle cell disease, polycythemia, and extreme
leukocytosis (e.g., chronic lymphocytic leukemia).

Some of the APR like CRP are unique because they can be used in cardiovascular risk assessment
for patients. It has also been shown in patients with acute coronary syndromes that elevated CRP
levels assayed by the high sensitivity (hsCRP) assay are indicative of poor cardiovascular prognosis.
Poor prognosis includes increased mortality, post-myocardial infarction, and unstable angina,
among others. In patients without ASCVD, a  hsCRP between 3 to 20 mg/L, on two occasions at least
six weeks apart, confers an increased risk for ASCVD provided a nidus for inflammation has been
excluded.[12]

CRP is a highly sensitive marker for detecting inflammation. It is not specific to any disease or
organ and has a half-life of 24 hours. In patients with systemic lupus erythematosus (SLE), CRP is
often within normal limits, and ESR is generally elevated. In SLE patients with elevated high-
sensitivity CRP (hsCRP), an infection should be ruled out because elevated hsCRP is a predictor for
active infection with high specificity in patients with SLE [13].

Giant-cell arteritis (GCA) is caused by the cell-mediated response to endothelial injury. It involves
monocytes differentiating into giant cells and macrophages within the vessel walls producing IL-6.
As mentioned above, IL-6 is an AP protein that mediates the systemic response to inflammation like
fever, weight loss, and causes the liver to produce other acute-phase proteins. It is also responsible
for elevated ESR in patients with GCA. Tocilizumab is an IL-6 receptor inhibitor that is used in
patients with GCA, and it can reduce relapses and lower glucocorticoid requirement to maintain
disease remission. [14]

Questions
To access free multiple choice questions on this topic, click here.

References
1. Gruys E, Toussaint MJ, Niewold TA, Koopmans SJ. Acute phase reaction and acute phase
proteins. J Zhejiang Univ Sci B. 2005 Nov;6(11):1045-56. [PMC free article: PMC1390650]
[PubMed: 16252337]
2. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N.
Engl. J. Med. 1999 Feb 11;340(6):448-54. [PubMed: 9971870]
3. Devaraj S, Singh U, Jialal I. The evolving role of C-reactive protein in atherothrombosis. Clin.
Chem. 2009 Feb;55(2):229-38. [PMC free article: PMC2662846] [PubMed: 19095731]
4. Bray C, Bell LN, Liang H, Haykal R, Kaiksow F, Mazza JJ, Yale SH. Erythrocyte Sedimentation
Rate and C-reactive Protein Measurements and Their Relevance in Clinical Medicine. WMJ. 2016
Dec;115(6):317-21. [PubMed: 29094869]
5. Samsudin I, Vasikaran SD. Clinical Utility and Measurement of Procalcitonin. Clin Biochem Rev.
2017 Apr;38(2):59-68. [PMC free article: PMC5759088] [PubMed: 29332972]
6. Schroedl W, Fuerll B, Reinhold P, Krueger M, Schuett C. A novel acute phase marker in cattle:
 lipopolysaccharide binding protein (LBP). J. Endotoxin Res. 2001;7(1):49-52. [PubMed: 11521082]
7. El Ghmati SM, Van Hoeyveld EM, Van Strijp JG, Ceuppens JL, Stevens EA. Identification of
haptoglobin as an alternative ligand for CD11b/CD18. J. Immunol. 1996 Apr 01;156(7):2542-52.
[PubMed: 8786317]
8. Jain S, Gautam V, Naseem S. Acute-phase proteins: As diagnostic tool. J Pharm Bioallied Sci. 2011
Jan;3(1):118-27. [PMC free article: PMC3053509] [PubMed: 21430962]
9. Kattula S, Byrnes JR, Wolberg AS. Fibrinogen and Fibrin in Hemostasis and Thrombosis.
Arterioscler. Thromb. Vasc. Biol. 2017 Mar;37(3):e13-e21. [PMC free article: PMC5324399]
[PubMed: 28228446]
10. Husebekk A, Skogen B, Husby G, Marhaug G. Transformation of amyloid precursor SAA to
protein AA and incorporation in amyloid fibrils in vivo. Scand. J. Immunol. 1985 Mar;21(3):283-
7. [PubMed: 3922050]
11. Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, Bouadma L, Luyt CE, Wolff M,
Chastre J, Tubach F, Kristoffersen KB, Burkhardt O, Welte T, Schroeder S, Nobre V, Wei L,
Bucher HC, Annane D, Reinhart K, Falsey AR, Branche A, Damas P, Nijsten M, de Lange DW,
Deliberato RO, Oliveira CF, Maravić-Stojković V, Verduri A, Beghé B, Cao B, Shehabi Y, Jensen JS,
Corti C, van Oers JAH, Beishuizen A, Girbes ARJ, de Jong E, Briel M, Mueller B. Effect of
procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a
patient level meta-analysis. Lancet Infect Dis. 2018 Jan;18(1):95-107. [PubMed: 29037960]
12. Ahmed MS, Jadhav AB, Hassan A, Meng QH. Acute phase reactants as novel predictors of
cardiovascular disease. ISRN Inflamm. 2012 May 06;2012:953461. [PMC free article:
PMC3767354] [PubMed: 24049653]
13. Firooz N, Albert DA, Wallace DJ, Ishimori M, Berel D, Weisman MH. High-sensitivity C-reactive
protein and erythrocyte sedimentation rate in systemic lupus erythematosus. Lupus. 2011
May;20(6):588-97. [PubMed: 21436216]
14. Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC,
Dasgupta B, Rech J, Salvarani C, Schett G, Schulze-Koops H, Spiera R, Unizony SH, Collinson N.
Trial of Tocilizumab in Giant-Cell Arteritis. N. Engl. J. Med. 2017 Jul 27;377(4):317-328.
[PubMed: 28745999]

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