What is Procalcitonin?
Procalcitonin (PCT) is a 116 amino-acid precursor hormone of calcitonin (molecular weight 13 kDa) that serves as a biomarker for bacterial infection, produced by parafollicular cells of the thyroid gland and neuroendocrine cells of the lung and intestine. 1
Biochemistry and Normal Physiology
PCT is normally produced in C-cells of the thyroid gland and intracellularly cleaved by proteolytic enzymes into active calcitonin. In healthy individuals, circulating PCT levels are below the detection limit, typically less than 0.05 ng/mL 1. The protein consists of 116 amino acids with a molecular weight of 13 kDa 2.
Pathophysiology in Infection
During bacterial infection, PCT production shifts dramatically:
- Production site changes: During inflammation, PCT is not produced in thyroid C-cells but rather in neuroendocrine cells of the lungs and intestine 1
- Induction mechanism: PCT production is triggered by bacterial endotoxin and inflammatory cytokines (TNF-α, IL-6) 2
- The liver is a major source of PCT production during inflammatory states 3
Kinetics and Timing
PCT demonstrates rapid response characteristics that distinguish it from other acute phase reactants:
- Begins rising 4 hours after bacterial exposure 1
- Reaches maximum levels at 6-8 hours 1
- Achieves half-maximal concentrations within 8 hours, which is 12 hours earlier than either serum amyloid A (SAA) or C-reactive protein (CRP) 3
- Decreases rapidly after antibiotic treatment 1
- Test results available within 1 hour with point-of-care testing devices or routine laboratories 1
Clinical Utility
PCT was discovered in 1993 as an elevated marker in patients with bacterial infection and has since become important for detection and differential diagnosis of inflammatory states 2.
Discriminatory Power
PCT was traditionally thought to discriminate systemic bacterial responses from viral and noninfectious etiologies. However, recent retrospective studies show PCT may be elevated during severe viral illness including influenza and COVID-19, potentially reducing its discriminating power for predicting causative microorganisms 1.
Correlation with Severity
Serum PCT levels are associated with the severity of infection 1, and studies have shown positive correlation with vasoactive drug requirements necessary to maintain cardiovascular activity in septic children 4.
Important Caveats
Non-Infectious Causes of Elevation
PCT elevation is not always due to bacterial infection:
- Medullary thyroid cancer metastases can synthesize and secrete PCT, leading to persistently elevated levels (>100 ng/L) independent of infection 5
- Elevated PCT may help diagnose or monitor cancer or inflammatory diseases 6
- Increases observed in acute renal failure or injuries 6
- Non-albicans Candida species and Plasmodium infections show significantly elevated PCT levels 7
Decreased Levels
PCT levels show notable decline in:
- Systemic infections caused by viruses (hepatitis B, hepatitis C) 7
- Cryptococcal species infections 7
- Skin commensal infections (coagulase-negative Staphylococcus, diphtheroids) 7
Comparison with Other Biomarkers
When compared to CRP in a systematic review and meta-analysis for sepsis diagnosis 1:
PCT performance:
- Area under SROC curve: 0.85 (95% CI, 0.82–0.88)
- Sensitivity: 0.80 (95% CI, 0.69–0.87)
- Specificity: 0.77 (95% CI, 0.60–0.88)
- Diagnostic odds ratio: 12.50 (95% CI, 3.65–42.80)
CRP performance:
- Area under SROC curve: 0.73 (95% CI, 0.69–0.77)
- Sensitivity: 0.80 (95% CI, 0.63–0.90)
- Specificity: 0.61 (95% CI, 0.50–0.72)
- Diagnostic odds ratio: 6.89 (95% CI, 3.86–12.31)
The literature does not strongly favor PCT over CRP or vice versa for routine use 1.
Mechanism of Action
There is no evidence of plasma PCT binding to cellular receptors of calcitonin, and the role of PCT in calcium and phosphate metabolism during sepsis remains unclear 2. Hypothetical roles include cytokine network regulation and functioning as an endogenous non-steroidal anti-inflammatory drug 2.
Classification as Acute Phase Protein
PCT behaves as a fast-responding acute phase protein both in vivo and in vitro 3. PCT and acute phase proteins like CRP are induced by similar pathways, with the liver appearing to be a major source of PCT production. The different kinetics of PCT, rather than a fundamentally different afferent pathway, may explain its diagnostic potential 3.