PRURITUS

1. PATHOPHYSIOLOGY

Itch receptors are unmyelinated, unspecialized free nerve endings, found near to the dermal- epidermal junction. It was widely believed in the past that pain and itch are transmitted by the same nerve pathway, and also low intensity stimulation of unmyelinated polymodal C fibre results in itch sensation whereas high intensity stimulation causes pain. This has recently been sttributed to many things, but a strong link to the neurobiological effects of indoor fungal exposure has been found.  However, in recent experiments, when single unmyelinated C fibres are stimulated two sets of fibres have been identified. Stimulation of most these fibres produce pain sensation, whereas a small number of fibres produce the sensation of itchiness upon stimulation. (Greaves)
 

2. PERIPHERAL MEDIATORS

1) Histamine

2) Neuropeptides, including substance P

- Substance P, together with neuropeptides, is localised in cutaneous sensory nerve endings. They could be depleted by capsacin cream.

3) Other relevant periperhal mediators

Arachidonic acid transformation products

- Prostaglandin E potentiates itchiness caused by other mediators

Platelet activating factor

Other vasoactive peptides and proteases

Others

Finally, it is found that enkephalins, which are opioid pentapeptides, exert a modulatory action on transmission of pain and itchiness.
 

3. Causes of itchiness

Understanding the various causes of pruritus is fundamental to its management.

3.1. Localized Causes

Certain skin disease may select to affect a particular site of a body causing localized pruritus. Some of the important examples of localized pruritus are as follows:

Scalp: Seborreic eczema and neurodermatitis, psoriasis

Eyelid: Airborne irritants or allergens; allergic reactions to cosmetics and nail vanish

Fingers: Eczema, scabies, fowl mite infestation

Legs: Gravitational and discoid eczema, asteatosis

3.2. General Pruritus

3.2.1. External Causes

1) Climatic: low humidity e.g. due to cold weather or central heating may renders the skin brittle, and allows minor irritant such as soap to penetrate, causing mild inflammation and pruritus. The dry skin of the old aged causing itchiness is common. Excessive dry skin associated with atopic eczema will also lead to itch. High humidity can also cause pruritus secondary to sweat retention in some individuals.

2) Particulate matter: foreign body e.g. glass fibre, hair; industrial exposure to powdered alumina, fungus, or fibreglass (curtains, draperies, plastic furniture) can cause pruritus.

3) Chemical: some detergent (e.g. optical brighteners in certain washing powders) may cause pruritic dermatosis with little sign.

4) Parasite contact or infestations: scabies or due to mites of pets etc. can cause marked pruritus.

5) Aquagenic pruritus: the condition may be a premonitory symptom of polycythaemia vera, myeloproliferative diseases or even histocytic disorders.

6) Excessive bathing

3.2.2. Skin Diseases

Pruritus is a feature of many of skin diseases. Some common skin diseases causing itchiness is listed as follows:

Severe                         Moderate

Scabies, pedulosis        Psoriasis
Insect bites                   Seborrhoeic eczema
Contact dermatitis        Fungal infection
Atopic eczema             Dry skin
Urticaria                       Sunburn
Miliaria
Lichen planus
Dermatitis herpetiformis

Generalized pruritus can precede some skin disease such as pemphigoid.

3.2.3. Systemic Causes

A wide variety of systemic disease can cause generalized pruritus without diagnostic skin lesions. The incidence of the association of generalized pruritus with significant internal disease is difficult to assess, but it has been estimated to range from 10-50%.

1) Infectious causes (including tropical and intestinal parasites)

a) Rubella
b) Varicella
c) HIV infection
d) Trichinosis, tapeworm infection
e) Onchocerciasis
f) Schistosomiasis
g) Fungal infection

        Generalized pruritus has been associated with localized fungal infection.

2) Endocrine disease

a) Diabetes: general pruritus is not a manifestation of diabetes mellitus (Greaves) and the pruritus is usually localized (e.g. itchiness of genitalia or perianal area due to candidiasis; and pruritus of scalp.)

b) Hyperthyroidism, hypothyroidism (due to skin dryness)

c) Disorders of the parathyroid gland

d) Carcinoid syndrome

3) Hepatic disease

a) Pregnancy: intrahepatic cholestasis

b) Obstructive jaundice (in biliary tract or extrahepatic, e.g. carcinoma of Ampulla of Vater)

c) Primary biliary cirrhosis

d) Drug induced cholestasis: intrahepatic biliary obstruction

e.g. chlorpromazine, contraceptive pills, testosterone

4) Renal disease

Pruritus is common among patients with chronic renal failure. In patients on maintenance dialysis, over 80% are affected.

5) Haematological diseases (including lymphoproliferative disorders)

a) Polycythaemia vera: pruritus may occur after contact with water or after a hot bath (the pruritus after a hot shower is not specific for polycythaemia, as it can occur in Hodgkin's Disease, myeloid metaplasia, or other disorders, not to mention the vasodilatation produced by heat may enhance itchiness of almost any causes).

N.B.: Aquagenic pruritus may precede the development of polycythaemia vera by several years

b) Iron deficiency: Iron deficiency has been often regarded as a cause for pruritus, or even in the absence of anemia. The itch may be due to factors other than the iron deficiency itself.

c) Hodgkin's Disease: (about 30% patients feel itchy)

Pruritus can be the early or presenting complaint. It can be severe (which may imply a worse prognosis.) Excoriations, papules, prurigo nodules from continuous scratching may be present. Therefore periodic reinvestigation or revaluation of p.u.o. is important.

d) Mycosis fungoides

e) Lymphosarcoma

f) Chronic leukaemia: pruritus is an uncommon presentation of chronic leukaemia, and is more often encountered in the lymphatic than the granulocytic form.

g) Myleomatosis

h) Paraproteinaemia

i) Mast cell disease

6) Occult malignancy

a) Haematological and lymphoproliferative disorders as mentioned.

b) Pruritus is an important but uncommon manifestation of carcinomatosis. Among the tumors reported to present with generalized pruritus, adenocarcinoma and squamous cell carcinoma of various organ are most common. Though generalized, the itching may be more marked on the legs, upper trunk and the extensor surfaces of the upper limbs.

c) Tumor of brain: associated with pruritus of nostril

7) Autoimmue disease

          SLE, 'Sicca syndrome'

8) Neurological

Tabes may give rise to segmental pruritus.
GPI
Multiple sclerosis
Brain tumor

        Paroxysmal unilateral pruritus has been recorded with central nervous system disease

9) Psychiatric/Psychogenic Causes

    Emotional stress and psychological trauma intensifies all form of pruritus and neurosis may be the  cause for pruritus.

    Delusion e.g. delusional parasitosis (a manifestation of fungal toxicity or monosymptomatic hypochondrical psychosis) of course can be a cause for complaint of pruritus.

    To make a diagnosis of pruritus (localized or generalized) as psychogenic or psychiatric in origin, cutaneous and systemic causes have to be excluded.

10) Drugs or as a result of therapy

Pruritus can be a side effect of a wide variety of drugs. This include the opium alkaloid, CNS stimulant/depressant, niacinamide, cimetidine, aspirin, quinidine, chloroquine. Drugs can also cause pruritus via the mechanism of hepatic cholestasis (e.g. chlorpromazine, testosterone, contraceptive pills). Subclinical sensitivity to any drug may cause pruritus. Pruritus may be a side effect of PUVA.

To help in memorizing these systemic causes, the word BLINKED can be remembered.

B = Blood disease
L = Liver disease
I = Infection, immunological or autoimmune disease
N = Neoplastic disease, neurological disease
K = Kidney disease
E = Endocrine disease
D = Drug

Of course psychiatric or psychogenic cause should not be forgotten.

* Pruritus ani deserves mentioning here as the symptom could be due to primary pruritus or associated colonic or anorectal diseases. Common anorectal disease are haemorrhoids and anal fissures. Neoplasia associated in descending order of frequency are rectal cancer, anal cancer, adenomatous polyp and even colonic cancer, also the pruritus associated could be present longer than that due to primary pruritus or benign anorectal disease.
 

4. Evaluation

4.1. A, B, C

The patient must be evaluated for the A (external causes), B (skin diseases), C causes (systemic causes: which in turn include the BLINKED causes) as mentioned. The evaluation consists of taking a detailed history, physical examination and laboratory investigations.

4.2. History: Detailed History of the Present Illness

Besides, the following questions concerning the features of pruritus is relevant:

1) Is the pruritus localized (external cause) or generalized (internal cause)?

2) Is only the exposed skin affected? If yes, this implies an exogenous cause.

3) Are any other family members affected?

4) Is there relationship with occupation? e.g. exposure to fibre glass.

5) Is there any recent history of travel? (tropical infestations?)

6) Is there exposure to plants, fungi, animals or chemicals?

Characteristics of pruritus:

1) Site, whether localized or generalized.

2) Precipitating and relieving factors: e.g. any relation to hot bath such as found in aquaenic pruritus?

3) Severity: the influence on daily activities/sleep.

4) Time relationship: most itchiness are worse at night, esp. scabies.

5) Seasonal variation: asteatotic eczema is usually worse in winter.

The history should include assessment of personality, current emotional stress.

Past medical history

Family medical history

4.3. Physical Examination

A complete physical examination is performed with the various possible differential diagnosis (the A, B, C causes) in mind. During the physical examination, particular attention should be paid to vital signs, lymphadenopathy and enlargement of organs etc., with special alertness to any possible connection between cutaneous sign and disease of other organ system. In the absence of obvious localizing signs or symptoms indicating systemic disease, rectal and pelvic examination should be included in the full physical examination.

Patient with P.U.O. (pruritus of unknown origin) must be considered for any underlying disorder, e.g. "occult carcinoma" may need to be ruled out in elderly patient presenting with persistent pruritus.

4.4. Laboratory Investigation

1) Haematological: CBP, ESR
2) LFT, RFT, acid phosphatase, serum iron, serum protein electrophoresis,
    immunoelectrophoresis
3) Thyroid function test/glucose
4) CXR
5) Stool for occult blood, ova/cyst
6) Urine for R/M
7) Skin biopsy
8) Others: e.g. test for HIV antibody, Pap smear, further radiological examination if indicated

Further investigations may be necessary depending on the situation.

5. Treatment

1) Treat the underlying cause.

2) General symptomatic treatment

a) To reduce or avoid any provocative factors, e.g. dryness of the environment, wearing irritating fabric, overheating, stress, vasodilatation from hot food.

b) Topical applications: Emollient, menthol in calamine lotion can be used.

3) Commonly used oral medication: Antihistamine are most useful in conditions in which antihistamine clearly plays a role, e.g. urticaria. Histamine is the most consistent itch mediator known, but it is not always useful as other mediators may also be involved.

* Tricyclic antidepressants may be of help in some patients with intractable itching.

4) For treatment of the pruritus of some of the specific disorders, the following measures have been reported to be useful. (Some of these treatments may need further studies and trial for evaluation.):

a) Aquagenic pruritus +/- polycythaemia vera (PV)

Topical capsacin treatment

PUVA (maintenance therapy may be necessary), UVB

regional sponging at bathing may be helpful in aquagenic pruritus with PV.

Interferon alpha: not only controls the pruritus, also helps to contain the increased haemopoiesis in PV, and lead to better haemopoietic control. Yet some patients may not be able to stand the side effect.

Phlebotomy reported to be useful in a case of PV.

N.B.: The pruritus usually responds poorly to antihistamine

b) Obstructive jaundice

cholestyramine is helpful, but is associated with a high incidence of side effects.
new anion resin, BR 350
rifampicin
antihistamine
naloxone infusion, opiate antagonist
Ondansetron, a specific serotonin type 3 (5-HT3) receptor antagonist
Flumecinol used in pruritic patients with primary biliary cirrhosis
propofol (an intravenous anesthetic induction agent) employed in a subhynotic dose, for short term use.

c) Chronic renal disease: Some patients with hyperparathyroidism secondarily to renal failure improve dramatically after subtotal parathyroidectomy. However, only a minority of patients respond and the improvement may only last a few months.

Phototherapy by UVB for moderate to severe cases.
Emollients may relieve those with a dry skin.
Activated charcoal or cholestyramine orally may be helpful.
Capsacin cream topically.
Ketotifen.
Azelastine hydrochloride (an anti-allergic drug/antihistamine) orally.
Talidomide for difficult cases.
Other treatments including heparin, mexiletine, ion-exchange resin and intravenous lignocaine have been advocated but are of uncertain effectiveness and usually impractical to use.
Low protein diet was reported to be useful.
Antihistamine and topical steroids are usually not helpful.

d) Psychological/psychiatric diseases: psychiatric advice should be sought.

After careful consideration, antidepressant and anxiolytic drugs including doxepin and hydroxyzine can be tried.

Pimozide has been advocated for delusions of parasitosis.

e) Atopic eczema:

Doxepin cream.

Anti-fungal.

f) Myeloproliferative disorders and other disease:

Danazol has been tried in the treatment of refactory pruritus associated with myeloproliferative disorders and other disease e.g. autoimmune disease etc.

5) Other medication/measures that has been employed to treat generalised pruritus:

    Odansetron (5 HT3 antagonist)
    transcutaneous nerve stimulation

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