Overview

Pruritus (pruor·rai·tuhs) is a term that is used to describe itchiness or itching. Itching can have a different number of causes, and so do its symptoms. As pruritus has differing causes relating to specific parts of the body, it is important to note any other symptoms you may be experiencing that can help medical professionals diagnose where the pruritus is coming from. This additional information can also help doctors analyse and check whether the pruritus is due to a serious disease, allergies, skin conditions, etc. Below, this article will describe the possible causes of pruritus, its symptoms, the different types of pruritus, relationships with diseases, and treatment options. 

What is Pruritus?

Pruritus is used to describe the feeling of needing to itch by medical professionals.¹ The biological mechanism for how itching works is still not completely understood for some types of pruritus, but there are quite a few studies on the signalling pathways [i.e. pathways that ‘signal’ the body’s cells to complete a cellular function ] that may be involved. Pruritus can be incredibly uncomfortable, and either acute (short-lived) or chronic (long durations) pruritus (> 6 weeks) affects 8–25.5% of the population in European studies.^2,3,4 Pruritus generally affects the older population (11–25%), and can severely impact the quality of life,⁵ with a study stating that patients with chronic pruritus had a worse quality of life in comparison to patients who had had a stroke.² It is important, however, to note the types of pruritus and their possible causes. The types of pruritus are as follows:

Types of pruritus:¹

• Skin-related (dermatological)
• Neuropathic (related to the nerves, caused by the nerves [e.g. nerve damage])
• Neurogenic (related to the nerves, caused by the nervous system)
• Psychogenic (caused by psychological factors)
• Mixed/Other pruritus (caused by different factors altogether)

Following the types of pruritus, itchiness can also be localised (found) in a specific area of the body, or generalised (found all over). 

Pruritus demographics

Pruritus is likely to affect the older generation due to their weakened skin barrier.¹ Additionally, women are more likely to get pruritus that can get worse from mental stress and nerve-related causes;^6,7 while men are more likely to experience pruritus at older ages and from systemic (biological system-related) disease.⁷ In terms of race and ethnicity, individuals of African and Asian descent are more likely to present with more severe cases of pruritus.⁷

Causes of pruritus

Skin-related pruritus

Within dermatological-caused pruritus, the cause of the itch can be grouped into the following categories along with several examples. Please note that not all examples are listed for the sake of simplicity:^1,8

• Inflammatory
  • Dry skin, atopic eczema, contact dermatitis, cutaneous (skin-related) amyloidosis, lichen planus, psoriasis, Grover disease
• Infections
  • Fungal, viral, bacterial, parasites (e.g. scabies) 
• Neoplastic
  • Non-melanoma skin cancer and T-cell lymphoma 
• Autoimmune (immune system attacking itself)
  • Cutaneous lupus, dermatitis herpetiformis 
• Genetic
  • Sjögren larsson syndrome, Hailey-Haliey disease
• Fibrosis-related
  • Scars (e.g. from injury), haemorrhoids

Systemic pruritus

Pruritus that is caused by a particular system (not including the nervous system) in the body is called ‘systemic pruritus.’ These include:^1,2

• Renal (kidneys): Uremic pruritus
• Endocrine (hormones)
• Haematologic (related to the blood) or oncologic (cancer-related)
• Rheumatologic (related to bones and joints)

Systemic pruritus can also be caused by bodily stresses, such as pregnancy and being older (predominantly in individuals over 60 years old).²

Neuropathic pruritus

Neuropathic pruritus accounts for around 8% of chronic pruritus patients and is commonly due to either nerve damage or the inability of the nervous system to regulate signals to the itchiness pathway.^1,2 Examples include forearm itchiness (brachioradial pruritus), mostly affecting middle-aged women.² 

Psychogenic pruritus

Although many studies have found that pruritus is correlated with depression and anxiety, the biological mechanism for how these mental disorders cause pruritus is still widely unknown.¹ Aside from mental disorders, the abuse of drugs such as opioids and cocaine has also been shown to cause pruritus.¹ 

Pruritus symptoms

Pruritus can be accompanied by the following symptoms:

• Dry skin (can also be cracked)
• Skin that feels leathery or thick (lichenification)
• Pain 
• Bleeding at the site of the itch
• Pus or infected skin
• Discolouration (either lighter or darker)
• Rash
• Pimple-like bumps (papules)
• Large bumps
• Blisters

Examples of underlying conditions

Pruritus can be indicative of underlying conditions that are not related to dermatological problems include:

• Diabetes
• Obsessive Compulsive Disorder (OCD)
• Allergies
• Liver disease (cholestasis)
• Thyroid-related diseases 
• Iron deficiency anaemia²
• Cancers
  • Specifically, polycythaemia vera (a type of blood cancer) 
  • Solid tumours

What makes something itchy?

Itchiness, on a biological level, can be caused by a multitude of factors. Pruritus was thought to predominantly be caused by histamines, and a breakthrough study in 1997 showed the existence of “C-receptors,” or C-fibre receptors. These C-fibres are composed of a group of nerves responsible for itchiness and neuropathic pain.⁹ The study found that introducing histamines into the skin activated these C fibres for durations that matched the participants’s itchiness.¹⁰ This confirmed the hypothesis that C fibres were responsible for the itch.¹⁰ For example, myelination is a term used to describe the outer sheath of a neuron’s axon that is used to speed up signals passing through the nerve. C-fibres were assumed to be unmyelinated,¹¹ because the blocking of myelinated (or sheathed) neuron activity did not stop histamine-induced pruritus. This was further confirmed by treating the skin with capsaicin (spice chemical), a chemical that temporarily prevents unmyelinated neurons from activating.¹⁰ Those treated with capsaicin were unable to feel itchiness.¹⁰ 

Histamine

Histamine is a chemical produced by white blood cells (specifically basophilic leukocytes) and mast cells. These cells are mediated (mediators: chemicals responsible for sustaining or starting a pathway)¹² by both inflammatory and non-inflammatory signals.¹ Once these signals reach these leukocytes or mast cells, histamine is produced which then binds to receptors such as the H1R (histamine-1-receptor) and H4R (histamine-4-receptor), which are receptors that are also present on C-fibres.¹

Following the 1997 breakthrough study, other studies found that histamines were not the only chemical responsible for the itch response. The mechanism/pathway that causes the itch overlaps.¹ All other chemicals have not been listed due to simplicity, but a few examples include:

Serotonin-induced pruritus

Serotonin is a mediator that can lead to histamine release due to its ability to indirectly activate mast cells.¹ The production of histamines subsequently causes pruritus. While serotonin is not usually a primary cause of pruritus, it can become one when induced by opioids.¹³ Specifically, serotonin (and other compounds) can activate neurons located in the spine.¹⁴ When opioids cause high levels of serotonin, these spinal neurons are activated, which can help relieve pain but also trigger itch signalling. This differs from the mechanism where histamine is produced by mast cells.¹⁴ 

Cytokines

Cytokines are proteins released by the immune system when the body is ‘under attack’ . These cytokines include proteins such as interleukins (IL), interferons, tumour necrosis factor, and more. Interleukins, particularly IL-2 and IL-6, are responsible for mediating histamine production.² In some cancers, like cutaneous T-cell lymphoma, the T-cells cause the secretion of cytokines such as IL-6.¹ Autoimmune disorders and allergies also cause an increase in cytokine production. In autoimmune disorders, this is due to the body attacking its own cells, while in allergies it results from the body’s response to foreign substances.¹⁵

Neuropathic nerve damage

In some diseases such as diabetes, patients are unable to control their blood sugar (glucose) levels. High levels of glucose can cause nerve damage, which leads to increased sensitivity of receptors that trigger itch signalling.¹⁶ 

Pruritus diagnosis and treatment

To try to rule out any severe diseases, your doctor will likely do a series of blood tests and imaging scans. These include:

• Allergy tests
• Blood tests (deficiencies, cancer, thyroid/liver diseases)
• X-rays
• Biopsies 

Depending on the type of pruritus and whether there are any underlying conditions, the treatment for pruritus will differ. For patients who have pruritus due to dry skin, moisturisers are recommended. Patients who are suffering from opioid-induced pruritus (after surgery, pregnancy or substance abuse), can be given naloxone, tenoxicam or diclofenac to relieve itching.¹⁷ For allergies, antihistamines can be prescribed to prevent further production of histamines.¹⁷

Summary

Itching/itchiness or pruritus can be caused by various diseases or external/environmental factors. These include cancers, allergies, diabetes, skin dryness and more. Predominantly, itchiness is attributed to the production of histamine which then binds to receptors on C-fibres that cause the itching sensation. However, other mediators exist that can cause pruritus, including serotonin, opioid use, nerve damage, stress, immune system disorders and more. Diagnosis of pruritus and its underlying conditions can include imaging scans, allergy tests and blood tests to check for any abnormal activities in the body. Treatment will then depend on the diagnosis, primarily aiming to treat the underlying condition.