Inflammatory markers

Figure 7.1: Cellular and exudative inflammation

The tissue damage elicits a cellular signal: CRP, to recruit and increase the number of neutrophils. To aid this process, the enzyme COX-2 produces prostaglandins, which cause constriction and dilatation at the site to affect blood flow. This response may cause pain (if a nerve is part of the constricted area), swelling, oedema and redness of skin.

Table 7.1: Inflammation analogies

Test: C-reactive protein (CRP)

Storytelling:

CRP is the ‘fire alarm’.

The more damage there is, the more alarms will sound and the more people will ring the fire brigade.

Once the fire-fighters are on site, the alarms may be switched off.

Interpretation:

CRP is relative to the degree of cellular damage. The more invasive the bacteria or trauma, the more CRP is produced.

If the blood test was requested post-injury, the CRP signal may be lost because the site of injury has been repaired.

Test: Neutrophils

Storytelling:

Neutrophils are the ‘fire engines’ that respond to CRP and cellular damage. The more damage there is, the more fire engines will be called.

A fire engine can also attend a fire without being called out, perhaps because the crew members have spotted a small fire on waste ground on the way back from a call (bacteria).

Interpretation:

Neutrophils respond to cellular damage but can also spontaneously destroy bacteria.

Test: Plasma viscosity (PV)

Storytelling:

As the fire engines and debris build up in the surrounding streets, the pressure in the area will increase. The more fire engines (neutrophils) and news reporters (bacteria, for example) there are, the more blocked the street will become.

Even after the fire alarm (CRP) has been switched off, the engines may stay at the site for a while. Neutrophils have a lifespan of two weeks so PV may be elevated after the initial CRP value.

Interpretation:

PV is a crude marker of material in the blood that increases pressure and ‘thickness’ or viscosity. The more cells and bacteria there are, the higher the PV.

PV can be useful to show that tissue injury occurred in the absence of a raised CRP.

Test: Erythrocyte sedimentation rate (ESR)

Storytelling:

Following a large fire, structural reinforcement is required. ESR indicates the amount of clotting around the damage site.

Interpretation:

In some autoimmune conditions that have relatively small amounts of tissue damage, such as rheumatoid arthritis (RA), ESR may be requested on a six-monthly basis because the damage is too small to affect the ESR.

Test: White blood cell count (WBC)

Storytelling:

The white cells are the ‘emergency vehicles’ (police cars and fire engines). As more fire engines (neutrophils) take to the street, the number of emergency vehicles on the roads increases. The WBC is the total number of white cells in circulation.

Interpretation:

WBC reflects inflammation. CRP, PV, ESR and white cell type. Increased neutrophils are likely to indicate a bacterial infection or an autoimmune response. Raised lymphocytes are likely to be due to viral infection.

Erythrocyte sedimentation rate

The erythrocyte sedimentation rate (ESR) is ‘how far red cells (erythrocytes) fall (sediment) in a tube, in an hour’. As the tissue is damaged, fibrinogen is released. Fibrinogen ‘sticks’ red cells together, making them heavy, so they fall further in the test. A high ESR means that more red cells are stuck together by fibrinogen, which results in more cell/tissue damage. ESR is usually raised in inflammation, but it can take time for this ‘sticking process’ to occur and indeed be removed. ESR is therefore not as quick to respond to damage as CRP. In some cases, ESR will rise in anaemia (independently of fibrinogen and inflammation). Large, macrocytic red blood cells will fall more quickly than small or normal-size ones. ESR can also be used to indicate cancer, myeloma and macrocytic anaemia and so could be being used for this reason. ESR also increases with age.

Storytelling: If you went to the top of a tall building and dropped three footballs (red cells), timing how long they took to fall, that would be a normal ESR. If you repeated this exercise, but placed the footballs in a heavy sack (fibrinogen resulting from inflammation), the balls would fall faster. However, as discussed earlier, ESR can also be independent of inflammation. If you repeated the demonstration, but dropped a large medicine ball (a macrocytic red blood cell) instead of three footballs, the large ball would fall faster. In other words, ESR can also be raised in macrocytic anaemia. You could cross-check ESR with mean cell volume (MCV) to find out the size of the red cells.

Plasma viscosity

Plasma viscosity (PV) is a measure of pressure in the blood (not blood pressure). It is measured in mPascals, a unit of pressure. PV is a surrogate marker of material that is not expected to be in the blood. As more white cells, bacteria, antibodies, red cells, in fact any material, build up in the blood, the pressure will rise and so will PV. It’s often described as ‘thick blood’ because more material is present.

Storytelling: Visualise a glass filled with water, and imagine stirring it with a spoon. The amount of pressure or power needed to stir the water is a normal PV. If you add a handful of marbles to the glass, it will be harder to stir because more pressure will be needed. Now imagine the glass is inside a box so you can’t see what is causing it to get harder to stir. It could be marbles (red blood cells), but it could also be stones (white blood cells) or woollen fibres (antibodies) or even sand (bacteria). Hence, an increased PV demonstrates an increase in pressure within the blood. But to determine the cause you’ll need to cross-check with other tests such as full blood count (FBC), looking at WBC, RBC and so on.

PV is mainly used to understand inflammation. It’s used in autoimmune conditions because it can indicate that additional antibodies and white cells are present, thickening or increasing pressure in the blood. PV can also be useful for monitoring against a baseline over time. However, it has limitations in that it is not specific to one disease and is therefore a crude global marker.

CRP

C-reactive protein (CRP) is a molecule that attracts and induces production of white blood cells (usually neutrophils), following inflammation. CRP is a marker for inflammation and infection and it can be used in autoimmune conditions because it can represent cellular signalling. CRP is also being used for chronic disease surveillance, as it is sensitive enough to represent vascular damage (raised CRP) and liver disease (low CRP). However, in some settings it can be expensive. Also, the signal can be lost as CRP is cleared, whilst ESR and PV may remain high for some time after the initial response.

The following storytelling offers a strategy to assist in interpreting a complex and dynamic process.

Storytelling: CRP is the fire alarm that goes off in the building, attracting fire engines (neutrophils/WBC) and causing a traffic jam in the street (PV). The structural support (fibrinogen scaffold) around the building is ESR. It’s unlikely that a small fire, as in the specific connective tissue damage caused by rheumatoid arthritis, will result in the entire building needing scaffolding. ESR is therefore only requested periodically, usually every six months. However, following major surgery or a large muscle trauma, ESR would be required.

Anti-inflammatory treatments

Anti-inflammatory treatments work along the pathways shown in Figure 8.1 (see page 59). Anti-TNF alpha treatments suppress the initial chemoattractant; drugs like methotrexate work by suppressing the neutrophil recruitment and replication (it was originally an anti-cancer cell proliferation drug); and drugs like aspirin and NSAIDS work to inhibit COX-2 and relieve the vasoconstriction.

To summarise, ESR represents tissue repair post-injury (fibrinogen), PV reflects components in the blood due to inflammation (more WBC, more antibodies), and CRP represents the tissue signalling in response to cellular damage.

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