Inflammatory Markers: hsCRP, ESR and Ferritin in Context

Inflammatory markers are ordered constantly, both to look for serious disease and, increasingly in functional practice, to assess low grade inflammation. They are useful, but they are not specific: a raised marker says that inflammation is present, not where or why. Understanding how each marker behaves allows practitioners to interpret them sensibly, to recognise when results disagree and to avoid both false alarm and false reassurance.

C reactive protein

C reactive protein is produced by the liver in response to inflammatory cytokines, particularly interleukin 6. It begins to rise within about 6 to 8 hours of an inflammatory stimulus, peaks at around 2 days and falls quickly once the stimulus resolves, because it has a short half life. It is therefore a good marker of acute and changing inflammation.

Standard CRP assays measure the higher concentrations seen in infection and active inflammatory disease. High sensitivity CRP assays measure lower concentrations accurately and are used to assess low grade inflammation. Values below 1 milligram per litre are generally considered low for cardiovascular risk purposes, 1 to 3 average and above 3 higher; values above 10 usually indicate an acute process, and the test should be repeated when the person is well.

In the JUPITER trial, people with normal LDL cholesterol but raised hsCRP had fewer cardiovascular events when treated with a statin, supporting the role of hsCRP in refining cardiovascular risk in some settings.

What raises CRP

• Infection, particularly bacterial
• Autoimmune and inflammatory diseases
• Tissue injury, surgery, burns
• Cancer
• Obesity and visceral adiposity
• Smoking, poor sleep, physical inactivity
• Oral oestrogen and pregnancy
• Periodontal disease

Erythrocyte sedimentation rate

The ESR measures how quickly red cells settle in a tube of blood. Inflammation increases fibrinogen and immunoglobulins, which cause red cells to clump and settle faster. The ESR rises and falls more slowly than CRP, over days to weeks.

Many factors other than inflammation affect it:

• it rises with age and is higher in women;
• anaemia raises it;
• pregnancy raises it;
• high levels of immunoglobulins or paraproteins, as in multiple myeloma, raise it markedly;
• abnormal red cell shapes, as in sickle cell disease, lower it.

A common rule of thumb estimates the upper limit of normal as age divided by 2 in men and age plus 10 divided by 2 in women. The ESR remains useful in specific conditions, such as polymyalgia rheumatica, giant cell arteritis and monitoring some autoimmune diseases.

Ferritin as an inflammatory marker

Ferritin reflects iron stores but also rises as part of the acute phase response. In inflammation, a normal ferritin can conceal iron deficiency, which is why higher ferritin thresholds, or transferrin saturation, are used to assess iron status when CRP is raised. Ferritin also rises with liver disease, alcohol and metabolic syndrome. Very high ferritin levels occur in some serious conditions, including haemophagocytic lymphohistiocytosis and adult onset Still disease, as well as iron overload.

When markers disagree

Systemic lupus erythematosus is a notable example: CRP is often only modestly raised in active lupus unless there is infection or serositis, while ESR is often raised. A high CRP in a patient with lupus should prompt consideration of infection.

Interpreting low grade inflammation

In functional practice, hsCRP is often used to identify low grade inflammation in people without acute illness. Principles for interpreting it include:

1. Confirm on repeat, ideally 2 measurements a few weeks apart, when the person is well.
2. Look for drivers: visceral adiposity, smoking, sleep apnoea, poor sleep, inactivity, periodontal disease, chronic infection, autoimmune disease, oral oestrogen.
3. Place it in cardiovascular risk, as one factor among many.
4. Track change after addressing drivers.
5. Avoid over interpreting single mildly raised values.

Other markers

Procalcitonin is used in hospital settings to help distinguish bacterial infection from other causes of inflammation and to guide antibiotic duration. Plasma viscosity is an alternative to ESR in some laboratories. White cell count and differential add information about the type of inflammatory response. Cytokine panels are research tools rather than routine clinical tests.

Red flags

• A markedly raised CRP or ESR with fever, weight loss, night sweats or localised symptoms
• A raised ESR with new headache, scalp tenderness, jaw pain or visual symptoms in an older adult, suggesting giant cell arteritis, which needs urgent assessment
• A very high ESR, which may indicate myeloma, infection, inflammatory disease or malignancy
• Very high ferritin without explanation

Worked cases

The persistent mild rise

A 49 year old man has an hsCRP of 4.5 and then 4.1 milligrams per litre 4 weeks apart, with no acute illness. He has central obesity, snores loudly and has bleeding gums. A sleep study confirms sleep apnoea, and a dental assessment finds periodontal disease. Addressing both, alongside weight loss, brings his hsCRP below 2 over 6 months.

The high ESR with normal CRP

A 72 year old woman with fatigue and back pain has an ESR of 85 with a normal CRP and mild anaemia. Her doctor checks serum protein electrophoresis, which reveals a paraprotein, and she is referred to haematology. The discordance was the clue.

The hidden iron deficiency

A 38 year old woman with rheumatoid arthritis and fatigue has a ferritin of 85 micrograms per litre, which appears normal, but her CRP is raised and her transferrin saturation is low. In this inflammatory context, iron deficiency is likely, and her doctor treats accordingly.

Markers, not diagnoses

Inflammatory markers tell practitioners that something is happening, not what it is. Knowing how CRP, ESR and ferritin behave, recognising discordant patterns and searching for the drivers of inflammation turn these simple tests into useful guides.