Clubbing pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The cause for sporadic clubbing is not known, and there are numerous theories as to its cause. Vasodilation (distended blood vessels), secretion of growth factors (such as platelet-derived growth factor and hepatocyte growth factor) from the lungs, and other mechanisms have been proposed. The discovery of disorders in the prostaglandin metabolism in primary osteo-arthropathy has led to suggestions that overproduction of PGE2 by other tissues may be the causative factor for clubbing.^[1] Many diseases are associated with clubbing such as oxygen deprivation and lung, heart, or liver disease.

Although many diseases are associated with clubbing such as oxygen deprivation and lung, heart, or liver disease, the reports are fairly anecdotal. Prospective studies of patients presenting with clubbing have not yet been performed, and hence there is no conclusive evidence of these associations.

• Lung disease:
  • Lung cancer, mainly large-cell (35% of all cases), not seen frequently in small cell lung cancer^[2]
  • Interstitial lung disease
  • Tuberculosis
  • Bronchiectasis
  • Suppurative lung disease: lung abscess, empyema
  • Cystic fibrosis
  • Pulmonary hypertension
  • Mesothelioma
  • It is worth noting that clubbing is not associated with chronic obstructive pulmonary disease (COPD). Indeed, the presence of clubbing in a patient with COPD should prompt a search for an underlying (lung) cancer.
• Heart disease:
  • Any disease featuring chronic hypoxia
  • Congenital cyanotic heart disease (most common cardiac cause)
  • Subacute bacterial endocarditis
  • Atrial myxoma (benign tumor)
• Gastrointestinal and hepatobiliary:
  • Malabsorption
  • Crohn’s disease and ulcerative colitis
  • Cirrhosis, especially in primary biliary cirrhosis^[3]
  • Other liver diseases (in the “hepatopulmonary syndrome”, a complication of cirrhosis)^[4]
• Others:
  • Hyperthyroidism (thyroid acropachy)^[5]
  • Familial and racial 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)
• HPOA
  • A special form of clubbing is hypertrophic pulmonary osteo-arthropathy, known in continental Europe as Pierre Marie-Bamberger syndrome. (In dogs the condition is known as hypertrophic osteopathy.) This is the combination of clubbing and thickening of periosteum (connective tissue lining of the bones) and synovium (lining of joints), and is often initially diagnosed as arthritis. It is commonly associated with lung cancer.
• Primary HOA
  • Primary hypertrophic osteo-arthropathy is HPOA without signs of pulmonary disease. This form has a hereditary component, although subtle cardiac abnormalties can occasionally be found. It is known in continental Europe as the Touraine-Solente-Golé syndrome. This condition has been linked to mutations in the gene on the fourth chromosome (4q33-q34)coding for the enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD); this leads to decreased breakdown of prostaglandin E2 and elevated levels of this substance.^[6]
• Secondary HOA
  • It is usually associated with lung cancer, pulmonary infections, cystic fibrosis, right-to-left cardiac shunts, and less often in Hodgkin’s lymphoma and cirrhosis. Among patients with lung cancer, HOA is most frequently associated with adenocarcinoma and least frequently with small cell carcinoma ^[7] Rarely, arterial vascular prosthesis infections may be associated with HOA^[8]. Clinical features suggestive of vascular infection-related HOA include clubbing or periosteal new bone formation in a single limb.

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