LO: Describe acute phase proteins and how they reflect inflammation

Inflammation

• Dolor - pain
• Calor - heat
• Rubor - redness
• Tumor - swelling
• Loss of function

Triggers

• C-reactive protein (CRP) - component of the complement cascade, C3
• Serum amyloid A
• Haptoglobin
• Fibrinogen
• Ferritin

Liver

• Protein synthesis is constantly in a state of turnover
• Nearly all proteins in blood made by the liver
• IL-1, IL-6 and TNF-alpha stimulate hepatocytes to produce acute phase reactants
• Acute phase proteins $\uparrow$ $\to$ Albumin levels $\downarrow$

Ferritin

• Rises with inflammation
• Acute phase reactant and marker of iron stores
• Marker of macrophage activation: very high levels in hyperinflammation
• Metabolic hyperferritinaemia: common in obesity and fatty liver disease - high ferritin without iron overload
• Links inflammation to ferroptosis, iron-dependent cell death
• Inflammation raises ferritin independently of iron stores

C-reactive protein (CRP)

• Pentraxin family of proteins
• Binds to Fc receptors of monocytes and neutrophils to stimulate production of cytokines and promote NETosis
• Works as an opsonin
• Activates complement

Target

• Pentameric (pCRP)
• Monomeric (mCRP)
• mCRP: pro-inflammatory, activates endothelium, monocytes and complement
• CRP apheresis after heart attack: safe, but primary endpoint not met
• Small-molecule CRP inhibitors protect tissue in ischaemia-reperfusion models

Complement

• Lectin pathway
• Classical pathway
• Alternative pathway

C3

• Activated by classic and alternative pathways
• Activates membrane attack complex: C5b, C6, C7, C8, C9
• Directly act in the process of inflammation
• Dilating arterioles
• Simulating mast cells to release histamine
• Chemotaxis of phagocytes
• Opsonisation of microbes

Serum Amyloid A (SAA)

• SAA1 acts as a powerful lipid detergent - solubilising membrane lipids into nanoparticles that engage receptors
• IL-6 main driver of hepatic serum amyloid A production
• Raised SAA can lead to AA amyloidosis - protein deposits in kidney, liver, spleen and gut
• IL-6 blockade (tocilizumab) normalises SAA and stabilise or regress AA amyloidosis
  mab - monoclonal antibodies

Clinical

• Acute phase reactants/proteins result of the processes of inflammation
• Inflammatory markers comprise of CRP and Erythrocyte sedimentation rate

Erythrocyte sedimentation rate (ESR)

• How fast erythrocytes clump together
• Non-specific sickness index
• Not diagnostic for any particular disease
• Increases with age - due to increase in SAA and anaemia
• Increases with increase in acute phase reactants and immunoglobulins
• Marker of chronic inflammation

CRP testing

• Antibiotic stewardship
• Reduces antibiotic prescribing for respiratory infections without harming recovery
• Biomarkers guide decisions, not make them

Sepsis six

• Bloods
• Measure urine output
• Check serial lactates
• Give IV fluids, abx, oxygen