Generalised itching

Generalised itching is pruritus over most of the body surface, with or without a primary rash.

Duration. Acute itch lasts under 6 weeks. Chronic itch lasts 6 weeks or longer and warrants a structured search for systemic disease.

Classification by skin findings. Group 1 is itch on primary diseased or inflamed skin. Group 2 is itch on apparently normal skin. Group 3 is chronic itch with secondary scratch lesions (excoriations, lichenification, prurigo nodules) and no identifiable primary lesion. Scratch damage can mask the original rash.

Classification by origin. Dermatological, systemic (renal, hepatobiliary, haematological, endocrine, infective, malignant), neurological, psychogenic, drug induced, mixed and undetermined.

Mechanisms. Histaminergic itch arises from mast cell degranulation acting on H1 receptors. It produces wheals and responds to antihistamines. Nonhistaminergic itch is driven by proteases, interleukin 31, thymic stromal lymphopoietin, substance P, bile salts, lysophosphatidic acid and an imbalance between mu and kappa opioid signalling. It responds poorly to antihistamines.

Transmission. Itch is carried by unmyelinated C fibres to the dorsal horn and spinothalamic tract. Scratching briefly suppresses itch through spinal inhibition, which maintains the itch scratch cycle.

Key distinctions. Itch before rash suggests systemic or neurological disease, while rash before itch suggests dermatosis. Nocturnal predominance is typical of scabies, cholestasis and atopic disease. Itch triggered by water of any temperature (aquagenic) is characteristic of polycythaemia vera.

History

• Onset, duration, course and diurnal pattern. Note the sleep disturbance.
• Initial distribution, symmetry, and whether itch preceded or followed the rash.
• Character (itch, burning, stinging, crawling) and triggers: water, heat, exercise, stress, wool, sweat, alcohol.
• Household or institutional contacts with itch, shared bedding, recent travel, animal exposure, new soaps, detergents, cosmetics, occupational exposures.
• Drugs started in the preceding 2 to 12 weeks, including over the counter and herbal products. Common culprits are opioids, hydroxyethyl starch (itch may start weeks after infusion and last months), chloroquine (frequent in patients of African descent, starts within days), aspirin, ACE inhibitors, calcium channel blockers, statins, thiazides, allopurinol, antiepileptics, amoxicillin with clavulanic acid, flucloxacillin, macrolides, chlorpromazine, anabolic steroids, oestrogen containing preparations, and targeted or checkpoint inhibitor cancer drugs.
• Systemic review: jaundice, pale stools, dark urine, weight loss, fever, night sweats, fatigue, lumps, bone pain, polyuria, polydipsia, heat or cold intolerance, flushing, diarrhoea, dyspnoea.
• Past history: atopy, kidney disease or dialysis, liver disease, diabetes, HIV, hepatitis B or C, malignancy, coeliac disease, previous helminth infection.
• Pregnancy status and gestation.
• Mood, anxiety, obsessional features, fixed belief of infestation, substance use.
• Residence in or travel to areas endemic for onchocerciasis, loiasis, schistosomiasis or strongyloidiasis.

Examination

• Full skin examination in good light: scalp, web spaces, wrists, axillae, umbilicus, genitalia, buttocks, feet, nails. Record dryness, scale, excoriations, lichenification, prurigo nodules, wheals, dermographism, burrows, nits, bullae, erythroderma, patches or plaques.
• Prurigo nodules spare the mid upper back (the butterfly sign) because it cannot be reached.
• Dermoscopy: the delta wing jet sign identifies a scabies mite at the end of a burrow.
• General signs: pallor, jaundice, koilonychia, facial plethora, xanthelasma, stigmata of chronic liver disease, lymph nodes in all regions, hepatosplenomegaly, thyroid size and signs, abdominal mass, breast examination.

Bedside tests. Urine dipstick (glucose, protein, blood, bilirubin), capillary glucose, scabies scraping with microscopy, skin snip in onchocerciasis endemic areas.

Red flags

• Itch with weight loss, fever, night sweats, lymphadenopathy or splenomegaly.
• Jaundice, pale stools, dark urine, or fever with right upper quadrant pain.
• New generalised itch without rash after 60 years of age.
• Aquagenic itch with facial plethora or burning of the hands and feet.
• Wheals with angioedema, stridor, wheeze or hypotension.
• Itch of the palms and soles in pregnancy.
• Bullae or urticarial plaques in an older adult.
• Erythroderma.
• Skin pain or mucosal erosions after a new drug.
• Suicidal thoughts related to itch or sleep loss.

Special groups

• Pregnancy: itch of the palms and soles at night after 28 weeks suggests intrahepatic cholestasis, which carries a risk of stillbirth.
• Older adults: xerosis, polypharmacy and pemphigoid are the commonest causes.
• Kidney impairment: itch is frequent in advanced disease and on dialysis.
• Region specific: onchocerciasis, loiasis, schistosomiasis, strongyloidiasis, chloroquine itch and HIV associated pruritic eruptions.

Skin disease with visible lesions

• Xerosis and asteatotic eczema: older adults, scaling and fissuring on the shins and trunk.
• Atopic dermatitis: flexural eczema, personal or family atopy.
• Scabies: nocturnal itch, burrows in web spaces and wrists, household contacts.
• Pediculosis corporis: itch at clothing seams, nits in garments.
• Chronic urticaria: wheals each lasting under 24 hours.
• Bullous pemphigoid, nonbullous phase: urticarial plaques and itch in older adults.
• Dermatitis herpetiformis: symmetrical excoriated papulovesicles on elbows, knees and buttocks.
• Morbilliform drug eruption.
• Pruritic papular eruption of HIV.
• Prurigo nodularis.
• Cutaneous T cell lymphoma (mycosis fungoides, Sezary syndrome): persistent patches or erythroderma.
• Lichen planus.
• Generalised contact dermatitis.
• Extensive tinea corporis.

Systemic causes with itch on normal skin

• Kidney: chronic kidney disease associated pruritus.
• Hepatobiliary: primary biliary cholangitis, primary sclerosing cholangitis, extrahepatic biliary obstruction (pancreatic head carcinoma, cholangiocarcinoma, gallstones), chronic hepatitis B, chronic hepatitis C, drug induced cholestasis.
• Haematological: iron deficiency, polycythaemia vera, Hodgkin lymphoma, non Hodgkin lymphoma, leukaemia, myelodysplastic syndromes, systemic mastocytosis, hypereosinophilic syndrome.
• Endocrine and metabolic: hyperthyroidism, hypothyroidism, diabetes mellitus, hyperparathyroidism, carcinoid syndrome.
• Solid malignancy: paraneoplastic itch (lung, gastrointestinal, breast, prostate, brain).
• Infection: HIV infection, strongyloidiasis, schistosomiasis, onchocerciasis, loiasis, hookworm infection.
• Neurological: small fibre neuropathy, multiple sclerosis, brain tumour, stroke.
• Other: coeliac disease, Sjogren syndrome, anorexia nervosa.

Drug induced and pregnancy related

• Drug induced pruritus (opioids, hydroxyethyl starch, chloroquine and others listed in the history).
• Intrahepatic cholestasis of pregnancy.
• Pemphigoid gestationis.
• Polymorphic eruption of pregnancy.
• Atopic eruption of pregnancy.

Psychogenic and idiopathic

• Depression, anxiety disorders, obsessive compulsive disorder and neurotic excoriation.
• Delusional infestation.
• Senile pruritus.
• Chronic pruritus of unknown origin: a diagnosis of exclusion after repeated evaluation.

Step 1. Establish whether primary skin disease is present. Examine the whole skin. Perform scabies scraping if burrows, nocturnal itch or contacts. Biopsy lesional skin if a persistent plaque or patch is present.

Step 2. Screen for systemic disease when the skin is normal or only scratched. First line tests:

• Full blood count with differential: eosinophilia suggests parasites, drugs, atopy, lymphoma or hypereosinophilic syndrome. Erythrocytosis suggests polycythaemia vera. Cytopenias suggest marrow disease.
• Ferritin: under 30 micrograms/L indicates iron deficiency in the absence of inflammation.
• Urea, creatinine and eGFR, electrolytes, calcium and phosphate.
• Liver tests: ALP, GGT, ALT, bilirubin. A raised ALP with GGT points to cholestasis.
• TSH, fasting glucose or HbA1c.
• Urinalysis.
• HIV test and, with risk factors, hepatitis B and C serology.
• ESR and CRP, which are raised in lymphoma and inflammatory disease.

Step 3. Targeted tests

• Antimitochondrial antibody and liver ultrasound for cholestasis; MRCP if the duct is dilated or primary sclerosing cholangitis is suspected.
• Fasting serum bile acids in pregnancy: over 10 micromol/L supports cholestasis, and 40 micromol/L or more marks severe disease.
• Chest radiograph and CT of chest, abdomen and pelvis for suspected lymphoma or occult malignancy; lymph node biopsy if enlarged.
• JAK2 V617F mutation if the haematocrit or haemoglobin is raised.
• Baseline serum tryptase: over 20 ng/mL suggests mastocytosis.
• Stool microscopy for ova and parasites, Strongyloides serology, and schistosomal serology or urine and stool microscopy where exposure is likely.
• Skin snips for onchocerciasis in endemic areas.
• Skin biopsy with perilesional direct immunofluorescence if pemphigoid is suspected; tissue transglutaminase IgA with total IgA if dermatitis herpetiformis is suspected.
• MRI brain or spine and nerve studies if neurological signs are present.

Interpretation and limits. Evidence is limited on the diagnostic yield of broad screening in itch with normal skin. A normal first screen does not exclude early lymphoma, cholestasis or mastocytosis. Repeat the evaluation at 3 to 6 months if itch persists. Diagnose psychogenic itch only after systemic causes are excluded.

Immediate. Itch with wheals and airway or circulatory compromise is anaphylaxis. Give adrenaline 0.5 mg (0.5 mL of 1 mg/mL) intramuscularly into the lateral thigh and repeat after 5 minutes if there is no response. Itch with erythroderma, fever and hypotension needs admission. Avoid systemic corticosteroids for undiagnosed itch, because they mask lymphoma and pemphigoid and prevent accurate biopsy.

General measures

• Emollients applied liberally at least twice daily, soap substitutes, short lukewarm showers, cotton clothing, cool bedroom, short nails.
• Menthol 1% in aqueous cream applied as needed for cooling.
• Aim to treat the cause, then add symptomatic drug therapy.

Cause directed

• Scabies: permethrin 5% cream to the whole body from the neck down (add scalp, face and ears in infants, older adults and immunocompromised patients), left on for 8 to 12 hours, then washed off. Repeat after 7 days. Treat all household and close contacts at the same time and launder bedding and clothes at 60 C. Itch may persist for 2 to 4 weeks after cure. Ivermectin 200 micrograms/kg orally with food, repeated after 7 days, is an alternative; it is not advised for children under 15 kg or in pregnancy. Avoid in Loa loa endemic regions without prior exclusion of high microfilaraemia.
• Iron deficiency: ferrous sulphate 200 mg (65 mg elemental iron) orally once daily or on alternate days. Continue for 3 months after haemoglobin normalises. Investigate the cause of the deficiency.
• Cholestatic itch: relieve obstruction (endoscopic stenting or surgery) when present. Drug therapy is stepwise:
• Colestyramine 4 g orally once daily before breakfast, increased to 4 g up to 3 times daily, usual maximum 24 g daily. Take other drugs at least 1 hour before or 4 to 6 hours after it. It is ineffective in complete biliary obstruction. Monitor for constipation and for vitamin A, D, E and K deficiency.
• Rifampicin 150 mg orally twice daily, titrated to 300 to 600 mg daily, maximum 600 mg daily (10 mg/kg). Exclude active tuberculosis first. Check liver tests at 2 and 4 weeks, then every 3 months; stop if transaminases rise over 5 times the upper limit or bilirubin rises. It induces CYP3A4 and lowers levels of warfarin, DOACs, hormonal contraception, ciclosporin and antiretrovirals. Urine and tears turn orange.
• Naltrexone 12.5 mg orally once daily, increased every 3 to 7 days to 50 mg daily (maximum 50 mg daily). Contraindicated with opioid use and in acute liver failure. Opioid withdrawal like symptoms can occur in the first days.
• Sertraline 25 to 50 mg orally once daily, titrated to 75 to 100 mg daily, as a further option.
• Chronic kidney disease associated pruritus: optimise dialysis adequacy and correct phosphate, calcium, parathyroid hormone and anaemia. Gabapentin 100 mg orally after each haemodialysis session (or 100 mg at night in advanced non dialysis disease), titrated to a maximum of 300 mg after each session. Monitor for sedation, dizziness and falls. Narrowband ultraviolet B phototherapy is an option. Difelikefalin 0.5 micrograms/kg intravenously at the end of each haemodialysis session where available.
• Polycythaemia vera: specialist treatment (venesection to haematocrit under 45%, low dose aspirin, cytoreduction) usually relieves itch.
• Thyroid disease, diabetes and hyperparathyroidism: correct the underlying disorder.
• Drug induced: stop the suspected drug if possible; itch from hydroxyethyl starch and opioids may persist.
• Neuropathic or unexplained chronic itch: gabapentin 300 mg orally at night, increased every 3 to 7 days to 900 to 1800 mg daily in 3 divided doses; maximum 3600 mg daily. Adjust for kidney function: creatinine clearance 30 to 59 mL/min, 400 to 1400 mg daily in 2 doses; 15 to 29 mL/min, 200 to 700 mg once daily; under 15 mL/min, 100 to 300 mg once daily. Reduce gradually over at least 1 week when stopping. Alternatives are pregabalin 25 to 75 mg daily (maximum 75 mg daily when creatinine clearance is under 15 mL/min, with a supplementary dose after haemodialysis) and mirtazapine 7.5 to 15 mg at night, maximum 45 mg daily.

Antihistamines. They help only histaminergic itch (urticaria) and as a sleep aid.

• Cetirizine 10 mg orally once daily, maximum 10 mg daily. Reduce to 5 mg daily when creatinine clearance is under 50 mL/min or in hepatic impairment. Avoid when under 10 mL/min.
• Loratadine 10 mg orally once daily; use 10 mg on alternate days in severe hepatic impairment or creatinine clearance under 30 mL/min.
• Hydroxyzine 25 mg orally at night, up to 25 mg three or four times daily, maximum 100 mg daily (50 mg daily in older adults). Short courses only. Avoid with QT prolongation or QT prolonging drugs, and in pregnancy. Halve the dose in moderate to severe kidney impairment.
• Chlorphenamine 4 mg orally every 4 to 6 hours, maximum 24 mg daily. Avoid in glaucoma, urinary retention and older adults.

Monitoring. Record itch intensity on a 0 to 10 scale and sleep at each review. Repeat tests at 3 to 6 months if no cause is found.

Referral and escalation

• Urgent haematology or lymphoma assessment (within 2 weeks) for itch with lymphadenopathy, splenomegaly, constitutional symptoms or abnormal blood count.
• Urgent hepatology or hepatobiliary review for cholestasis; same day admission for suspected cholangitis (fever, jaundice, right upper quadrant pain).
• Obstetric review within 24 hours for suspected cholestasis of pregnancy.
• Dermatology for suspected pemphigoid, cutaneous lymphoma, dermatitis herpetiformis, erythroderma or refractory itch.
• Nephrology for dialysis related itch.
• Psychiatry for delusional infestation.

Admission. Anaphylaxis, erythroderma, cholangitis, haemodynamic instability, severe sleep deprivation or suicidal ideation.

Follow up. Review at 2 to 4 weeks to assess response. Safety net advice: return for jaundice, fever, weight loss, new lumps, breathlessness, rash with skin pain or blistering, or reduced foetal movements in pregnancy.