Summary

Digital clubbing was first described by Hippocrates in patients with empyema more than 2000 years ago. Since then, it has been recognised 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).

Definition

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 hyper-extensible. [1]

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.

Pathophysiology

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, oedema, 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 extra-pulmonary 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. [1] [2]

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. [3] 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. [4] [5]

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. [4] In addition, clubbing may be stimulated by local arteriovenous anastomoses provoked by neurocirculatory stimuli. Conditions that involve chronic platelet excess (e.g., inflammatory bowel disease) result in peripheral platelet trapping and release of PDGF. [4]

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.