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PRURITUS
1. PATHOPHYSIOLOGY
Itch receptors are unmyelinated, unspecialized free nerve endings, found near to the dermal-epidermal junction.
It was proposed by Rothman and others, and 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. However, in recent experiments, two populations of fibres have been identified when single unmyelinated C fibres are stimulated, a majority which respond by causing pain sensation and a small minority stimulation of which causes itch. (Greaves).
Itch-transmitting, polymodal, unmyelinated C fibre enter the dorsal horn of the gray matter of the cord, synapse there with secondary neurons which cross over to the contralateral spinothalamic tract and ascend to the thalamus. There, tertiary neurons relay the sensation of itch to the level of consciousness in the cortex.
Psychoneurophysiological aspects of itching are complex and poorly understood. The involvement of large, fast-conducting myelinated sensory fibres in modulation of the discharge of the unmyelinated itch- or pain-transmitting fibres presynaptically as proposed by Melzack and Wall (gate control of pain) is generally acknowledged. However, the more recent discovery of enkephalins has complicated the picture. These opioid pentapeptides (including leu-enkephalin and met-enkephalin, which are extensively distributed in the peripheral and central nervous system, are capable of stimulating the opioid receptors in the central nervous system) exert a regulatory action on pain and itch traffic through the central nervous system. Stimulation of these receptors down regulate pain but may up-regulate itch. Naloxone, a synthetic opioid antagonist, may however, relieve intractable pruritus. The opioid peptides may also be important peripherally. Intradermal injection of a stable met-enkephalin analogue in a concentration which by itself was subthreshold for itching, potentiated histamine-evoked itching. Met-enkephalin-like immuno-reactivity is also present in Merkel cells which serve a neuroreceptor function.
2. PERIPHERAL MEDIATORS
2.1 Histamine
Histamine causes itching if injected into the skin. Three subclasses of histamine receptors are identified. The histamine H3 subclass acts as autoreceptors regulating release and biosynthesis of histamine in brain slices and other tissues but they have yet to be identified in the skin. Both H1- and H2-receptors have been found in human skin in studies which have implicated H1- but not H2-receptors is involved in histamine induced itching. Thus there is no theoretical basis for use of H2-antagonist (cimetidine, ranitidine) in the suppression of itching caused by histamine. The majority of histamine released in skin arise as a result of injury of the dermal mast cells.
2.2 Neuropeptides
Substance P causes redness, wealing and itching. It selectively releases histamine and not prostaglandin D2 or other mast cell products from human mast cells in vitro. However, topical capsaicin application, which is known to deplete substance P from sensory nerve endings, abolishes pain and itch. Substance P is co-localise with other neuropeptides including calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) in cutaneous sensory nerve endings but the involvement of CGRP and VIP in itch has not been explored. Substance P is synthesised in the dorsal root ganglion of nociceptor C fibres and transmitted peripherally in granules in the sensory nerve endings.
2.3 Other Vasoactive Peptides and Proteases
Studies have shown that endopeptidases possess the property of inducing itch. Several investigators have considered the possibility that the peptide product of proteases might be important mediators of itching, but no potent itch-producing peptide released by protease activity in-situ has been isolated from the human skin.
2.4 Arachidonic Acid Transformation Products
Inflammation of human skin is associated with the transformation of cell membrane arachidonic acid into a variety of proinflammatory fatty acid products and this include the prostaglandins and others. Prostaglandin E shows little or no pruritic activity in human skin. However, it has the property of potentiating itching due to other mediators in concentration (the prostaglandin) which by themselves have no visible pro-inflammatory activity. There were studies reporting that PGE1 potentiates itch due to histamine or other substances. Increased skin concentrations of prostaglandin E have been reported in eczema and UVB inflammation, both of which are associated with pruritus.
2.5 Platelet Activating Factor
Platelet activating factor is released from a variety of inflammatory cells, with powerful pro-inflammatory properties. Studies in human skin suggest that any pruritus generated by platelet activating factor is likely to be indirect, and consequent upon its histamine-liberating action on cutaneous mast cells.
2.6 Factors Modulating Itching
The 'gate control system' has been mentioned. Psychological factors may act on this system. Warmth exacerbating itching has a physiological basis, conferring a rationale on cooling as a method of controlling itching. Cooling acts directly on sensory receptors, whereas heating stimuli appears to act centrally.
3. CAUSES OF ITCHINESS
Understanding the various causes of pruritus is fundamental to its management.
3.I Localized Causes
Certain parts of the body may have a predilection for certain disease processes which may thus present as localized pruritus. Some of the important examples of localized pruritus are as follows:
Scalp : Eczema-especially seborrhoeic and contact, neurodermatitis, psoriasis
Eyelid : Airborne irritants or allergens; allergic reactions to make-up and nail vanish
Nose : Hay fever
Fingers : Eczema, scabies, fowl mite infestation
Legs : Gravitational and discoid eczema, asteatosis
3.2 General Pruritus
(A) External Causes
(i) 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.
(ii) Particulate matter - foreign body, hair, glass fibre, industrial exposure to powdered alumina or fibreglass (curtains, draperies, plastic furniture) can cause pruritus.
(iii) Chemical - some detergent (e.g. optical brighteners in certain washing powders) may cause pruritic dermatosis with minimal sign.
(iv) Parasite contact or infestations - scabies or due to mites of pets etc. can cause marked pruritus.
(v) Aquagenic pruritus - the condition may be a premonitory symptom of polycythaemia vera. Investigation of affected skin has shown increased histamine concentrations and increased mast cell degranulation. The lack of visible evidence of histamine release can be explained by the slow rate of release leading to skin concentration sufficient to cause itching but subthreshold for visible vascular changes. Besides histamine, there is evidence of involvement of acetylcholine as a mediator.
(vi) Excessive bathing
(B) Skin Diseases
Pruritus is a feature of a wide variety of skin diseases. Some common skin diseases causing itchiness is listed as follows:
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Severe
- Scabies, mite infestations
- Pediculosis, insect bites, etc.
- Contact and atopic eczema
- Urticaria and dermographism
- Prickly heat
- Lichen planus
- Dermatitis herpetiformis
- Toxic eruption
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Moderate
- Psoriasis
- Seborrhoeic
- eczema
- Pityriasis rosea
- Sunburn
- Fungal disease
- Asteatotic skin
- Urticaria pigmentosa
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Generalized pruritus can precede some skin disease such as pemphigoid. Xerosis is associated with pruritus.
(C) 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%.
(i) Infectious causes (including tropical and intestinal parasites)
(a) Rubella (b) Varicella
(c) Trichinosis (d) Onchocerciasis
(e) Schistosomiasis (e) Fungal infection
(generalized pruritus has been associated with localized fungal infection)
(ii) 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
(iii) 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
(iv) Renal disease
Pruritus is common among patients with chronic renal failure. In patients on maintenance dialysis, over 80% are affected.
(v) 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 neither sensitive nor 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).
(NB : Water induced itching may precede the development of polycythaemia vera by several years )
(b) Iron deficiency - Iron deficiency has been frequently implicated as a cause of intractable pruritus in the absence of visible skin disease, or even in the absence of anemia. Patients with iron deficiency not infrequently complain of pruritus, however the present data suggest that the itch is likely 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
(vi) 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
(vii) Autoimmue disease
SLE, 'Sicca syndrome'
(viii) Neurological
Tabes may give rise to segmental pruritus.
GPI
Multiple sclerosis
Brain tumor
Paroxysmal unilateral pruritus has been recorded with central nervous system disease
(ix) 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 monosymptomatic hypo-chondrical 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.
(x) 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
Psychiatric or psychogenic cause should not be forgotten.
4. EVALUATION
4.1 A, B, C
The patient must be evaluated for the A, B, C 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 :
(i) Is the pruritus localized (external cause) or generalized (internal cause)?
(ii) Is only the exposed skin affected? If yes, this implies an exogenous cause.
(iii) Are any other family members affected?
(iv) Is there relationship with occupation? e.g. exposure to fibre glass.
(v) Is there any recent history of travel? (tropical infestations?)
(vi) Is there any pets or animal exposure?
(vii) Any history of exposure to chemicals, plants?
Characteristics of pruritus
(i) Location (localized or generalized)
(ii) Provocating and relieving factors - e.g. any relation to hot bath such as found in polycythaemia rubra vera?
(iii) Character - e.g. burning type of itchiness could occur in DH.
(iv) Severity - the influence on daily activities. Would it wake the patient up from sleep?
(v) Time relationship - most itchiness are worse at night, esp scabies.
(vi) Seasonal variation - asteatotic eczema is usually worse in winter.
(vii) Assessment of personality, emotional stress.
(viii) Past medical history
(ix) 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 organomegaly 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 PUO (pruritus of unknown origin) must be considered to have an underlying disorder until proven otherwise.
Visceral carcinoma should be suspected in elderly patients with bullous eruption and pruritus; indeed persistent pruritus in any elderly patient should always arouse the suspicion of an 'occult carcinoma'.
4.4 Laboratory Investigation
(i) Haematological
CBP, ESR, serum iron, serum protein electrophoresis, immuno-electrophoresis
(ii) LFT, RFT, acid phosphatase
(iii) Thyroid function test/glucose
(iv) CXR
(v) Stool for occult blood, ova/cyst
(vi) Urine for R/M
(vii) Skin biopsy
(viii) Others - e.g. Pap smear, further radiological examination if indicated
Further investigations may be necessary depending on the situation
5. TREATMENT
(i) Treat the underlying cause.
(ii) The treatment of the pruritus of some of the specific disorders is as follows:
(a) Aquagenic pruritus - the pruritus responds poorly to antihistamine treatment but may respond to UVB and phototherapy.
(b) Obstructive jaundice - cholestyramine is helpful, but is associated with a high incidence of side effects. Other advocated methods include phenobarbitone and rifampicin, plasmaphoresis and phototherapy.
(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 is frequently effective.
* Emollients may relieve those with a dry skin.
* Activated charcoal or cholestyramine orally may be helpful.
* 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) Polycythaemia vera - Regional sponging at bathing may decrease the itch.
* Successful treatment of the underlying polycythaemia may not relieve the itching and although correction of the venesection-induced iron deficiency may give relief, the polycythaemia may be exacerbated.
* Antihistamines are generally ineffective.
* UVB irradiation and aspirin have been successful in some patients (Greaves).
(e) 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.
(iii) 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.
(iv) 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 since it is not the only mediator it is not surprising that antihistamines are not always helpful.
* Tricyclic antidepressants may be of help in some patients with intractable itching.
(v) Special treatment
(a) Naloxone, a synthetic opioid antagonist (hence a possible specific antipruritic drug), may relieve intractable pruritus. It is being used experimentally in some cases.
(b) Topical capsaicin is being tried in some centres as a antipruritic agent.
(vi) Other suggested measures of uncertain efficacy include transcutaneous nerve stimulation and acupuncture.
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