New-Onset Pruritus in Adults: The Often-Missed Diagnoses

Dr Neeraj Manikath , claude.ai

Abstract

Pruritus, or itch, is a common yet frequently overlooked symptom that can significantly impact quality of life and may herald serious underlying systemic disease. While dermatological causes remain predominant, clinicians must maintain vigilance for the subtle presentations of systemic, neurological, and psychogenic etiologies that are often missed in initial evaluations. This review focuses on the diagnostic approach to new-onset pruritus in adults, emphasizing commonly overlooked diagnoses and providing practical clinical pearls for the internist.

Introduction

Pruritus affects 8-15% of the general population and represents one of the most common reasons for dermatology referrals. However, approximately 10-50% of chronic pruritus cases have an underlying systemic cause, making this symptom a crucial diagnostic challenge for internists. The pathophysiology involves complex interactions between peripheral and central mediators, including histamine, proteases, opioids, and cytokines acting on C-fibers and specific itch receptors.

Pearl #1: The absence of a rash does not exclude dermatological disease. Primary skin diseases can present with pruritus before visible lesions appear, and secondary changes from scratching (excoriations, lichenification, prurigo nodularis) often obscure the original pathology.

Systematic Approach to the Patient with Pruritus

Initial Assessment

The evaluation begins with a comprehensive history focusing on:

• Onset, duration, and temporal pattern (nocturnal, seasonal)
• Distribution (localized vs. generalized)
• Associated symptoms (fever, weight loss, fatigue, arthralgia)
• Medication history (including over-the-counter drugs and supplements)
• Occupational and environmental exposures
• Travel history
• Family history of atopy or systemic diseases

Hack #1: Ask about water-induced pruritus (aquagenic pruritus) specifically. This symptom, occurring within minutes of water contact, is highly suggestive of polycythemia vera but often goes unreported unless directly queried.

Physical examination should assess:

• Skin lesions: primary vs. secondary
• Signs of systemic disease: jaundice, lymphadenopathy, hepatosplenomegaly
• Dermographism
• Xerosis (often coexistent and contributory)

The "Often Missed" Diagnoses

1. Hematological Malignancies

Hodgkin's Lymphoma

Pruritus occurs in 10-30% of Hodgkin's lymphoma patients and may precede other symptoms by months or years. The itch is characteristically severe, generalized, and refractory to standard antihistamines.

Oyster: In a young adult with unexplained generalized pruritus, particularly if nocturnal sweats are present, Hodgkin's lymphoma should be considered even in the absence of palpable lymphadenopathy. The pruritus may involve the lower extremities preferentially and can be triggered by alcohol consumption.

Initial workup should include complete blood count, peripheral smear, lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), and chest radiograph. If clinical suspicion persists despite negative initial tests, consider CT imaging and consultation for lymph node biopsy.

Polycythemia Vera

Aquagenic pruritus is present in 40-70% of polycythemia vera patients. The pathophysiology involves increased histamine release from basophils and mast cells, compounded by elevated levels of prostaglandins.

Pearl #2: A normal hemoglobin does not exclude polycythemia vera. Early disease, concurrent iron deficiency, or recent phlebotomy can mask elevated red cell mass. Check JAK2 mutation testing if clinical suspicion is high.

Cutaneous T-Cell Lymphoma (Mycosis Fungoides)

Early-stage mycosis fungoides frequently presents with nonspecific eczematous patches that are intensely pruritic. The diagnosis is often delayed by 3-6 years due to its resemblance to benign dermatoses.

Hack #2: Consider mycosis fungoides when "eczema" is asymmetric, affects sun-protected areas (buttocks, breasts, trunk), or is refractory to appropriate topical steroids. Repeat biopsies may be necessary, as initial histology can be nondiagnostic.

2. Endocrine and Metabolic Disorders

Chronic Kidney Disease

Uremic pruritus affects 20-50% of dialysis patients but can occur earlier in CKD progression. The pathophysiology is multifactorial, involving uremic toxins, xerosis, secondary hyperparathyroidism, and systemic inflammation.

Pearl #3: Pruritus in CKD patients correlates poorly with urea levels but shows stronger associations with elevated parathyroid hormone (PTH) and C-reactive protein (CRP). Screen all pruritic CKD patients for secondary hyperparathyroidism.

Management includes optimizing dialysis adequacy, moisturizers, topical antipruritic agents, phototherapy (narrowband UVB), gabapentin (100 mg post-dialysis), and considering calcimimetics for elevated PTH.

Thyroid Dysfunction

Both hyperthyroidism and hypothyroidism can cause pruritus. Hyperthyroidism increases cutaneous blood flow and sweat production, while hypothyroidism causes xerosis. The pruritus typically resolves with restoration of euthyroid status.

Diabetes Mellitus

Beyond localized genital candidiasis, diabetes can cause generalized pruritus through small fiber neuropathy, autonomic dysfunction affecting sweat glands, and increased skin pH favoring bacterial colonization.

3. Hepatobiliary Diseases

Primary Biliary Cholangitis (PBC)

Pruritus is the presenting symptom in 25% of PBC cases and eventually affects 70% of patients. It characteristically begins on the palms and soles, is worse at night, and may precede jaundice by months to years.

Oyster: A middle-aged woman with pruritus and fatigue warrants screening for PBC even with normal bilirubin. Check antimitochondrial antibodies (AMA) and alkaline phosphatase. AMA positivity exceeds 90% sensitivity.

The pathophysiology involves increased bile acid levels and elevated autotaxin, which produces lysophosphatidic acid—a potent pruritogen.

Treatment hierarchy:

1. Bile acid sequestrants (cholestyramine 4-16 g/day, taken away from other medications)
2. Rifampin 150-300 mg twice daily (monitor liver enzymes)
3. Naltrexone 25-50 mg daily (start low due to opioid withdrawal-like effects)
4. Sertraline 75-100 mg daily

Hack #3: When prescribing cholestyramine, advise patients to take it at least 4 hours away from other medications, as it impairs absorption. Consider switching to colesevelam (better tolerated, fewer drug interactions).

Intrahepatic Cholestasis of Pregnancy (relevant for female patients of reproductive age)

This typically presents in the third trimester with pruritus involving palms and soles, often without rash. Elevated bile acids confirm diagnosis. While resolving postpartum, it has implications for fetal outcomes.

4. Infectious Etiologies

Human Immunodeficiency Virus (HIV)

Pruritus affects 20-30% of HIV-infected individuals, may be multifactorial (xerosis, eosinophilic folliculitis, drug reactions, infections), and often correlates with lower CD4 counts.

Scabies

Pearl #4: Classic distribution (web spaces, wrists, axillae, waistline, genitalia) may not be present in "Norwegian" or crusted scabies, which occurs in immunocompromised patients and presents with hyperkeratotic plaques rather than typical burrows.

Hack #4: In institutional outbreaks or immunocompromised patients with refractory pruritus, empiric treatment for scabies is reasonable even with negative scrapings, as sensitivity of microscopy is only 30-50%. Treat close contacts simultaneously.

Parasitic Infections

Helminthic infections (hookworm, strongyloidiasis, onchocerciasis) can cause pruritus through eosinophilia and immune activation. Consider in patients with appropriate travel history or immigration from endemic areas.

5. Neurological Causes

Neuropathic Pruritus

Brachioradial Pruritus

This affects the lateral arms and is associated with cervical radiculopathy (C5-C6) or prolonged sun exposure. Examination may reveal hyperpigmentation without primary lesions.

Oyster: Ice pack application providing relief is pathognomonic for brachioradial pruritus and distinguishes it from dermatological causes.

Treatment includes cervical spine evaluation, avoiding sun exposure, topical capsaicin, gabapentin, or pregabalin.

Notalgia Paresthetica

Presents as unilateral pruritus and hyperpigmentation in the mid-back (T2-T6 distribution), often associated with thoracic vertebral pathology. Like brachioradial pruritus, it responds to neuropathic pain medications.

Small Fiber Neuropathy

Pearl #5: Consider small fiber neuropathy in patients with generalized pruritus and paresthesias without large fiber signs (normal reflexes, vibration, proprioception). Skin biopsy for intraepidermal nerve fiber density is diagnostic.

6. Psychogenic and Somatoform Disorders

Delusional Parasitosis

Patients have fixed false beliefs of infestation, often bringing samples of "specimens" (matchbox sign). Requires tactful psychiatric referral and possible antipsychotic therapy (pimozide, risperidone).

Psychophysiologic Pruritus

Real pruritus exacerbated by stress, anxiety, or depression. Up to 30% of chronic pruritus patients have underlying psychiatric comorbidity. Consider when temporal patterns correlate with stressors and standard treatments fail.

7. Drug-Induced Pruritus

Commonly Implicated Medications:

• Opioids (via mu-receptor activation)
• Hydroxyethyl starch (can cause severe delayed pruritus)
• Antimalarials (chloroquine particularly in dark-skinned individuals)
• Statins
• ACE inhibitors
• Allopurinol
• Antibiotics

Hack #5: When evaluating drug causation, consider agents started 2-3 months prior to symptom onset. Some drug reactions have prolonged latency periods.

Diagnostic Algorithm

First-Line Investigations

• Complete blood count with differential
• Comprehensive metabolic panel
• Thyroid-stimulating hormone
• Liver function tests including alkaline phosphatase
• Chest radiograph
• HIV serology (with appropriate counseling)

Second-Line Investigations (based on clinical suspicion)

• Serum protein electrophoresis
• Antimitochondrial antibodies
• Ferritin and iron studies
• LDH, ESR
• JAK2 mutation testing
• Serum IgE levels
• Stool ova and parasites (with travel history)
• Skin biopsy (for atypical presentations)

Advanced Investigations

• CT chest/abdomen/pelvis (for occult malignancy)
• Bone marrow biopsy
• Nerve conduction studies and skin biopsy for small fiber neuropathy
• Punch biopsy for cutaneous T-cell lymphoma

Management Principles

General Measures

1. Optimize skin barrier: Emollients within 3 minutes of bathing (soak and seal technique)
2. Avoid triggers: Hot water, harsh soaps, wool clothing, low humidity
3. Menthol-based topicals: Provide temporary cooling relief through TRPM8 receptor activation

Symptomatic Pharmacotherapy

Topical Agents:

• Corticosteroids (for inflammatory component)
• Calcineurin inhibitors (steroid-sparing)
• Capsaicin 0.025-0.1% (neuropathic pruritus)
• Doxepin cream (H1/H2 antagonist)

Systemic Therapy:

• Nonsedating antihistamines: Limited efficacy except in urticaria
• Gabapentin 300-2400 mg/day: First-line for neuropathic and uremic pruritus
• Pregabalin 75-300 mg/day: Alternative to gabapentin
• Mirtazapine 15-30 mg at bedtime: Dual benefit for pruritus and sleep
• Aprepitant: NK1-receptor antagonist, emerging option for refractory cases
• Phototherapy: Narrowband UVB for multiple etiologies

Pearl #6: Antihistamines work primarily through sedation rather than direct antipruritic effects in most non-urticarial pruritus. Don't escalate to dangerous doses; if first-generation antihistamines at standard doses fail, pivot to other drug classes.

Red Flags Requiring Urgent Investigation

• Constitutional symptoms (fever, night sweats, weight loss)
• Rapidly progressive symptoms
• Lymphadenopathy or organomegaly
• Abnormal complete blood count
• Jaundice
• New-onset pruritus in elderly patients (higher malignancy risk)
• Associated neurological symptoms

Conclusion

New-onset pruritus in adults demands systematic evaluation beyond superficial dermatological assessment. The internist must maintain a broad differential, including hematological malignancies, metabolic derangements, occult malignancies, and neuropathic causes. A thorough history focusing on associated symptoms, temporal patterns, and medication review, combined with targeted initial investigations, usually identifies or excludes serious systemic disease. For refractory cases, multidisciplinary collaboration involving dermatology, hematology, and other subspecialties optimizes diagnostic yield and therapeutic outcomes.

Final Hack: Create a "pruritus clinic" approach—see patients back in 2-4 weeks after initial workup. Many diagnoses declare themselves with time, and reassessment with fresh eyes often reveals previously missed clues.

References

1. Yosipovitch G, Bernhard JD. Chronic pruritus. N Engl J Med. 2013;368(17):1625-1634.

2. Weisshaar E, Dalgard F. Epidemiology of itch: adding to the burden of skin morbidity. Acta Derm Venereol. 2009;89(4):339-350.

3. Ständer S, Weisshaar E, Mettang T, et al. Clinical classification of itch: a position paper of the International Forum for the Study of Itch. Acta Derm Venereol. 2007;87(4):291-294.

4. Zirwas MJ, Seraly MP. Pruritus of unknown origin: a retrospective study. J Am Acad Dermatol. 2001;45(6):892-896.

5. Krajnik M, Zylicz Z. Understanding pruritus in systemic disease. J Pain Symptom Manage. 2001;21(2):151-168.

6. Yosipovitch G, Goon A, Wee J, Chan YH, Goh CL. The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. Br J Dermatol. 2000;143(5):969-973.

7. Mettang T, Kremer AE. Uremic pruritus. Kidney Int. 2015;87(4):685-691.

8. Kremer AE, Bolier R, van Dijk R, et al. Advances in pathogenesis and management of pruritus in cholestasis. Dig Dis. 2014;32(5):637-645.

9. Dugas-Breit S, Schöpf P, Dugas M, Schiffl H, Ruëff F, Przybilla B. Baseline serum levels of mast cell tryptase are raised in hemodialysis patients and associated with severity of pruritus. J Dtsch Dermatol Ges. 2005;3(5):343-347.

10. Beauregard S, Gilchrest BA. A survey of skin problems and skin care regimens in the elderly. Arch Dermatol. 1987;123(12):1638-1643.

---

Word count: 2,000

Disclosure: No conflicts of interest to declare.