Nail clubbing

Did You Know?

• The Dutch painter Dick Ket had nail clubbing, as is seen from his paintings; he had an underlying disease, probably dextrocardia.
• Clubbing has been called 'Hippocratic fingers'.

Causes

Clubbing is associated with lung disease including lung cancer, interstitial lung disease most commonly idiopathic pulmonary fibrosis, complicated tuberculosis, suppurative lung disease (lung abscess, empyema, bronchiectasis, cystic fibrosis), mesothelioma of the pleura, and sarcoidosis. Heart disease causes include any disease featuring chronic hypoxia, cyanotic heart defect (the most common cardiac cause), infective endocarditis, atrial myxoma, and arteriovenous fistula or malformation. Gastrointestinal and hepatobiliary associations include malabsorption, Crohn's disease and ulcerative colitis, cirrhosis especially in primary biliary cholangitis, and hepatopulmonary syndrome. Other causes are Graves' disease (known as thyroid acropachy), familial and hereditary clubbing and pseudoclubbing (people of African descent often have what appears to be clubbing), vascular anomalies of the affected arm such as an axillary artery aneurysm (in unilateral clubbing), and primary hypertrophic osteoarthropathy. Nail clubbing is not specific to chronic obstructive pulmonary disease (COPD); in patients with COPD and significant clubbing, a search for bronchogenic carcinoma or other causes may be indicated. A special form is hypertrophic pulmonary osteoarthropathy (HPOA), also called Pierre Marie-Bamberger syndrome, combining clubbing with thickening of periosteum and synovium, often initially diagnosed as arthritis and commonly associated with lung cancer. Primary hypertrophic osteoarthropathy (HPOA without pulmonary disease) has a hereditary component and is known as Touraine–Solente–Golé syndrome, linked to mutations in the gene on chromosome 4q33-q34 coding for 15-hydroxyprostaglandin dehydrogenase (HPGD) or mutations in SLCO2A1.

Pathogenesis

Most cases of nail clubbing appear linked to increased levels of platelet-derived growth factor (PDGF) and/or vascular endothelial growth factor (VEGF) signaling at the fingertips, causing vascular hyperplasia, capillary permeability, and excessive fibroblast and osteoblast formation. Specific causes include increased entry of megakaryocytes into the systemic circulation; normally trapped in the pulmonary capillary bed, they bypass breakdown in disorders with extrapulmonary shunting (e.g., cyanotic heart diseases, liver cirrhosis) and release PDGF and VEGF in the digits. In diffuse pulmonary diseases or lung cancer, excess VEGF produced in diseased lungs directly enters circulation. Hypoxia induces VEGF expression by platelets and enhances release of PDGF and VEGF by megakaryocytes. Other causes include overproduction of prostaglandin E by other tissues (e.g., in lung cancer and Crohn's disease, linked to higher COX-2 levels), underconsumption of prostaglandin E in HPGD and/or SLCO2A1 mutations (pachydermoperiostosis), use of prostaglandin E medication, and chronic excess of platelets in inflammatory bowel disease. In thyroid acropachy, the explanation leans autoimmune, likely involving increased fibroblast proliferation and deposition of glycosamines. The cause is unclear in sarcoidosis, where clubbing is rare and occurs in an advanced fibrotic stage. The exact pathogenesis in hemiplegia is unknown aside from blood flow alterations due to autonomic nervous system instability; the vagus nerve may play a role in cases linked to inflammatory bowel disease and/or lung cancer. The exact cause of sporadic clubbing is unknown.

Diagnosis

Before confirming clubbing, doctors first rule out pseudoclubbing. A detailed history focusing on lung, heart, and gastrointestinal issues, plus a full physical exam, can uncover related conditions. Chest X-rays or CT scans may detect hidden cardiopulmonary problems. Clubbing progresses through five stages. In the first stage, only the nail bed feels soft and wobbly, with no visible change. Mild clubbing shows a lost Lovibond angle (normally under 165 degrees) and a closed Schamroth’s window, but isn’t obvious at first glance. Moderate clubbing makes the nail fold more curved and visible right away. Gross clubbing thickens the entire fingertip, making it look like a drumstick. The final stage, hypertrophic osteoarthropathy, gives the nail and skin a shiny, striated appearance. A common check is Schamroth’s sign: pressing the same fingernails of opposite hands together normally creates a small diamond-shaped gap between the nailbeds. If that gap disappears, clubbing is present.