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ULY CLINIC

25 Mei 2025, 18:03:26

Clubbing

Clubbing is a painless, bilateral hypertrophy of the soft tissues of the distal digits (fingers and toes) characterized by increased curvature and swelling of the nail bed and terminal phalanges without bony deformity. The hallmark is loss of the normal angle (~160°) between the nail plate and proximal nail fold, which increases toward 180° or more.

Pathophysiology

Clubbing results from chronic tissue hypoxia and altered vascular dynamics in the distal digits.
Proposed mechanisms:
- Increased blood flow to the distal phalanges mediated by vasodilatory prostaglandins (particularly PGE2).
- Platelet-derived growth factors released into systemic circulation due to pulmonary shunting or vascular abnormalities → stimulate connective tissue proliferation.
- Hypoxia induces vascular endothelial growth factor (VEGF) release → neovascularization and fibroblast proliferation.
Genetic mutations (e.g., in SLCO2A1 or HPGD genes) can cause isolated or primary hypertrophic osteoarthropathy with clubbing.

Clinical presentation

Early: Soft tissue swelling at nail base, nail bed feels spongy ("floating nail" sign).
Progression: Nail bed thickens, angle increases >180°, nails become convex both longitudinally and transversely ("drumstick" appearance).
Late: Increased bulbous enlargement of distal digits ("watch-glass nails").

Diagnostic Approach

History

Review symptoms of underlying cardiopulmonary disease (e.g., chronic cough, dyspnea, cyanosis, fever, weight loss).
Duration and progression of clubbing.
Family history for congenital or inherited forms.
Medication, occupational, or environmental exposures.

Physical Examination

Measure nail angle with a goniometer if available.
Look for associated signs: cyanosis, peripheral edema, chest deformities.
Examine all digits including toes.
Evaluate for signs of infective endocarditis (Osler nodes, Janeway lesions), heart failure (JVD, edema), or pulmonary disease (crackles, wheezing).

Diagnostic Tests

Pulse oximetry and arterial blood gases: To assess oxygenation status.
Chest X-ray / CT scan: To identify pulmonary causes (bronchiectasis, interstitial fibrosis, lung abscess, neoplasms).
Echocardiography: To evaluate for cyanotic congenital heart disease, infective endocarditis, or heart failure.
Laboratory tests: CBC (anemia, infection), inflammatory markers, blood cultures (endocarditis), sputum analysis.
Genetic testing: If primary hypertrophic osteoarthropathy or congenital clubbing suspected.

Differential diagnosis

Condition	Distinguishing Features
Primary hypertrophic osteoarthropathy	Familial, isolated clubbing with periostosis and arthritis, normal cardiopulmonary function.
Curved nails (normal variant)	Nail angle remains ~160°, no soft tissue swelling.
Thyroid acropachy	Clubbing with pretibial myxedema, usually in Graves' disease.
Psoriatic arthritis	Clubbing-like changes, but with skin and joint symptoms.
Acromegaly	Enlarged hands/feet but different morphology.

Common medical causes of clubbing

The table below shows common medical causes of clubbing

Condition	Typical Features & Associated Signs
Bronchiectasis	Late-stage clubbing, cough with copious foul-smelling mucopurulent sputum, hemoptysis, coarse inspiratory crackles, weight loss, fatigue, dyspnea, rhonchi, fever, halitosis.
Chronic Bronchitis	Late sign, chronic productive cough, barrel chest, dyspnea, wheezing, accessory muscle use, cyanosis, tachypnea, crackles, rhonchi, prolonged expiration.
Emphysema	Late stage, anorexia, malaise, dyspnea, tachypnea, diminished breath sounds, peripheral cyanosis, pursed-lip breathing, barrel chest.
Infective Endocarditis	Subacute form, fever, anorexia, weakness, night sweats, fatigue, tachycardia, weight loss, arthralgia, petechiae, Osler’s nodes, splinter hemorrhages, Janeway lesions, splenomegaly, Roth’s spots, cardiac murmurs.
Heart Failure	Late sign, wheezing, dyspnea, fatigue, jugular vein distension, hepatomegaly, tachypnea, palpitations, dependent edema, weight gain, nausea, hypotension, diaphoresis, narrow pulse pressure, gallop rhythm, inspiratory crackles.
Interstitial Fibrosis	Advanced disease, intermittent chest pain, dyspnea, crackles, fatigue, weight loss, possible cyanosis.
Lung Abscess	Clubbing reversible with treatment, pleuritic chest pain, dyspnea, crackles, productive foul-smelling bloody sputum, halitosis, weakness, fever, chills, weight loss, decreased breath sounds.
Lung & Pleural Cancer	Commonly causes clubbing, hemoptysis, dyspnea, wheezing, chest pain, weight loss, anorexia, fatigue, fever.

Clinical implications

Clubbing indicates chronic hypoxia or chronic systemic disease and warrants thorough investigation.
May precede other clinical signs of underlying disease or indicate disease progression.
Persistent clubbing despite therapy may suggest irreversible tissue changes or undiagnosed disease.

Management

Treat the underlying cause aggressively (e.g., antibiotics for infection, surgery for congenital heart defects or lung abscess, chemotherapy for lung cancer).
Monitor progression or regression of clubbing as an indicator of disease control.
Patient education: Clubbing is not harmful by itself but is a marker for significant systemic disease.
Referral to specialists (pulmonologists, cardiologists, oncologists) as indicated.

Pediatric and geriatric considerations

Pediatrics

Common in cyanotic congenital heart disease and cystic fibrosis.
Surgical correction may reverse clubbing.

Geriatrics

Arthritic changes or deformities may mask or confuse diagnosis.
Careful clinical evaluation is needed.

Recent research and genetic insights

Mutations in SLCO2A1 (prostaglandin transporter) and HPGD (prostaglandin degradation enzyme) genes are linked to hereditary primary hypertrophic osteoarthropathy with clubbing.
These findings help differentiate primary (genetic) from secondary (acquired) clubbing and open pathways for targeted therapies.

Summary table: Key features of clubbing in major diseases

Disease	Clubbing Onset	Associated Clinical Signs	Reversibility
Bronchiectasis	Late	Copious sputum, hemoptysis, crackles	Possible with treatment
Chronic Bronchitis	Late	Barrel chest, chronic productive cough, cyanosis	Usually irreversible
Emphysema	Late	Dyspnea, pursed-lip breathing, barrel chest	Usually irreversible
Infective Endocarditis	Variable	Fever, murmurs, petechiae, Osler nodes, splenomegaly	Reversible with antibiotics
Heart Failure	Late	JVD, edema, tachypnea, gallop rhythm	Depends on cardiac function
Interstitial Fibrosis	Advanced	Dyspnea, crackles, weight loss	Usually irreversible
Lung Abscess	Initial	Foul sputum, fever, chest pain	Usually reversible
Lung/Pleural Cancer	Variable	Weight loss, hemoptysis, chest pain	Usually irreversible

References

Seifert et al. (2012). Mutations in SLCO2A1 gene cause primary hypertrophic osteoarthropathy and digital clubbing. Human Mutations, 33, 660–664.
Tariq et al. (2009). Mutation in HPGD gene causing isolated congenital nail clubbing. Journal of Medical Genetics, 46(1), 14–20.
Seifert W, Kühnisch J, Tüysüz B, Specker C, Brouwers A, Horn D. Mutations in the prostaglandin transporter encoding gene SLCO2A1 cause primary hypertrophic osteoarthropathy and isolated digital clubbing. Hum Mutat. 2012;33(4):660–4.
Tariq M, Azeem Z, Ali G, Chishti MS, Ahmad W. Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC). J Med Genet. 2009;46(1):14–20.
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Fishman AP, Elias JA, Fishman JA, Grippi MA, Senior RM, Pack AI, editors. Fishman’s Pulmonary Diseases and Disorders. 5th ed. New York: McGraw-Hill; 2015.
Mandell GL, Bennett JE, Dolin R, editors. Principles and Practice of Infectious Diseases. 9th ed. Philadelphia: Elsevier; 2020.