Clubbing (Digital Clubbing / Hippocratic Fingers)

Clubbing of all fingers (Fishman's Pulmonary Diseases)

Close-up of clubbed nails showing characteristic curvature (Andrews' Diseases of the Skin)

Definition

• Harrison's Principles of Internal Medicine 22E
• Fishman's Pulmonary Diseases and Disorders

Clinical Features (How to Recognize It)

• Andrews' Diseases of the Skin; Murray & Nadel's Textbook of Respiratory Medicine

Pathogenesis

1. Vasodilation and arteriovenous shunting - A humoral substance (or substances) that would normally be inactivated by the pulmonary capillaries escapes into the peripheral circulation, causing vasodilation of vessels in the fingertip and forming arteriovenous connections. This raises hydrostatic pressure in capillaries and venules, promoting fluid transudation into the interstitium. This explains clubbing in cyanotic heart disease, hepatic cirrhosis (with pulmonary AV anastomoses), and various lung diseases.
2. Angiogenic growth factors - Histochemical studies show increased VEGF (vascular endothelial growth factor), PDGF (platelet-derived growth factor), HIF-1α, and HIF-2α, along with markedly increased microvessel density in the stroma of clubbed digits. Platelet precursors (megakaryocytes) that bypass the pulmonary filter may release these growth factors directly in the digital circulation.
3. Prostaglandin pathway (hereditary form) - Mutations in HPGD (encoding NAD+-dependent 15-hydroxyprostaglandin dehydrogenase) and in the prostaglandin transporter gene SLCO2A1 have been identified in primary/hereditary clubbing, suggesting prostaglandin excess plays a role.

• Murray & Nadel; Fishman's; Andrews' Diseases of the Skin

Causes

Not Associated with Overt Disease

• Hereditary/familial clubbing (dominant trait)
• Sporadic clubbing
• Pachydermoperiostosis (primary hypertrophic osteoarthropathy)

Thoracic - Most Common Category

• Lung cancer (single most common acquired cause)
• Bronchiectasis
• Cystic fibrosis
• Lung abscess / empyema
• Idiopathic pulmonary fibrosis (IPF) / asbestosis
• Sarcoidosis
• Tuberculosis
• Mesothelioma
• Other thoracic neoplasms (esophageal cancer, lymphoma)

Important: COPD does NOT cause clubbing. Clubbing in a COPD patient should prompt a search for lung cancer.

Cardiac / Vascular

• Cyanotic congenital heart disease
• Subacute bacterial endocarditis (infective endocarditis)
• Pulmonary arteriovenous fistula / hereditary hemorrhagic telangiectasia
• Takayasu's arteritis, Behçet syndrome
• Infected aortic graft

Gastrointestinal / Hepatic

• Inflammatory bowel disease (Crohn disease, ulcerative colitis)
• Hepatic cirrhosis / biliary cirrhosis
• Hepatopulmonary syndrome
• Polyposis coli, hepatoma

Other

• HIV infection (~36% of HIV-infected patients)
• Thyroid acropachy
• Hemoglobinopathies / congenital methemoglobinemia
• Secondary hyperparathyroidism
• Toxic exposure (arsenic, mercury, beryllium)
• Voriconazole (drug-induced)
• Jackhammer operators (occupational)
• Murray & Nadel eTable 18.1; Harrison's; Andrews'

Unilateral / Asymmetric Clubbing

• Subclavian artery aneurysm
• Brachial AV fistula
• Median nerve injury
• Local trauma
• Hemiplegia
• Ipsilateral pulmonary sulcus (Pancoast) tumor invading the brachial plexus
• Takayasu arteritis, sarcoidosis

Hypertrophic Osteoarthropathy (HOA)

• Painful, symmetric arthritis-like changes at shoulders, knees, ankles, wrists, elbows
• Periosteal new bone visible on X-ray or MRI; hot on bone scan (99mTc-MDP)
• Most strongly associated with: bronchogenic carcinoma, mesothelioma, cystic fibrosis, bronchiectasis

Clinical Significance and Workup

• Clubbing was found in ~1% of internal medicine admissions and was associated with serious underlying disease in 40% of cases.
• New-onset clubbing always warrants a chest X-ray, and if unrevealing, a CT scan to exclude pulmonary neoplasm.
• Clubbing can develop rapidly (within ~2 weeks, e.g., new empyema) and reverse similarly (e.g., after cardiac surgery, lung transplant for CF, or treatment of lung cancer).

Summary Mnemonic: CLUBBING