Digital clubbing was first described by Hippocrates in patients with empyema more than 2000 years ago. Since then, it has been recognized as an important nail sign of systemic disease linked with underlying pulmonary, cardiovascular, neoplastic, infectious, hepatobiliary, mediastinal, endocrine, and gastrointestinal disorders. Digital clubbing may also occur in isolation (e.g., familial clubbing, as an autosomal-dominant trait).
Clubbing is described as a bulbous uniform swelling of the soft tissue of the terminal phalanx of a digit with subsequent loss of the normal angle between the nail and nail bed. View imageView image The first stage of clubbing is a periungual erythema and a softening of the nail bed; this is followed by an increase in the Lovibond angle (the angle between the proximal nail fold and the nail plate). View image Eventually the depth of the distal phalange increases and the distal interphalangeal joint may become hyperextensible.  The Schamroth window test can be used to identify or confirm clubbing. If 2 opposing fingers are held back to back against each other, a diamond-shaped space should normally appear between the nail beds and the nails of the 2 fingers. In clubbing, this space (or window) is missing.
Clubbing is usually bilateral, although unilateral clubbing does exist (e.g., axillary artery aneurysm and brachial arteriovenous malformations). It is painless unless associated with underlying conditions such as pulmonary hypertrophic osteoarthropathy. The vast majority of patients are unaware of its presence. However, an understanding of the causation and diseases associated with clubbing alerts the physician to the seriousness of this sign and the need to investigate the patient appropriately.
Several theories exist to explain causation and risk factors. Advances in the study of the pathogenesis have established that vascular endothelial growth factor (VEGF) is key. This platelet-derived factor is stimulated by hypoxia and produced in diverse malignancies and conditions that affect circulation. VEGF induces vascular hyperplasia, edema, and fibroblast or osteoblast proliferation at a peripheral level in the nails. In primary pulmonary conditions such as lung cancer, this is the operative mechanism. When there is extrapulmonary shunting of blood - for example, in cyanotic heart disease - large megakaryocytic fragments gain access to the systemic circulation and affect distal sites such as the nails. Here, these fragments release their growth factors, including VEGF.  
This mechanism does not explain all causes of clubbing. Unilateral clubbing secondary to local disorders (e.g., axillary artery aneurysm) is not due to a pulmonary circulation defect.  In cases of bronchogenic carcinoma, growth hormone has been implicated as a cause of clubbing. In hypertrophic osteoarthropathy, an additional unknown factor is considered necessary to produce this syndrome, while others think that cyanosis is also required.  
A neural mechanism involving the vagal system has also been proposed, following the observation that pathology and disease of vagally innervated organs is associated with an increased incidence of clubbing and that clubbing may be reversed following vagotomy. This has been especially noted in cases with hypertrophic osteoarthropathy. However, this hypothesis is now decreasing in popularity.
Another prominent theory explaining the mechanism behind clubbing focuses on the role of platelet-derived growth factor (PDGF). Platelets release PDGF in the vasculature of the fingertips. PDGF stimulates growth, vascular permeability, and monocyte and neutrophil chemotaxis, and leads to proliferation of vascular smooth muscle cells and fibroblasts, as is seen in clubbing.  In addition, clubbing may be stimulated by local arteriovenous anastomoses provoked by neurocirculatory stimuli. Conditions that have chronic platelet excess (e.g., inflammatory bowel disease) result in peripheral platelet trapping and release of PDGF. 
As clubbing is a manifestation of several disorders, no single genetic factor predisposes to clubbing. The heredity of each disorder is distinct. Not all are genetic.
- Cystic fibrosis
- Interstitial pulmonary fibrosis
- Pleural mesothelioma
- Cavitating pulmonary TB
- Pulmonary metastases
- Atrial myxoma
- Axillary artery aneurysm
- Brachial arteriovenous malformations
- Thyroid acropachy
- Severe secondary hyperparathyroidism
- Hodgkin lymphoma
- Disseminated chronic myelogenous leukemia
- Ulcerative colitis
- Crohn disease
- Primary biliary cirrhosis
- Thyroid cancer
- Thymus cancer
- Lipoid pneumonia
- Pulmonary artery sarcoma
- Ulcerative esophagitis
- Celiac disease
- Tropical sprue
- Leiomyoma of the esophagus
- Familial clubbing
- Pachydermoperiostosis (primary hypertrophic osteoarthropathy)
- Secondary hypertrophic osteoarthropathy
- Palmoplantar keratoderma