Clinical Sign: Clubbing

Background

Since Hippocrates first described digital clubbing in patients with empyema, digital clubbing has been associated with various underlying pulmonary, cardiovascular, neoplastic, infectious, hepatobiliary, mediastinal, endocrine, and gastrointestinal diseases. Finger clubbing also may occur, without evident underlying disease, as an idiopathic form or as a mendelian dominant trait.

Definition

“Clubbing” is a clinically descriptive term, referring to the 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 the nail bed.

Classification

Digital clubbing is classified into primary (i.e., idiopathic, hereditary) and secondary forms. Digital clubbing may be symmetric bilaterally, or it may be unilateral or involve a single digit.

Method of Examination

Anatomic considerations, such as the classic measurement of the Lovibond angle or the more recently derived index of nail curvature by Goyal et al, usually can be identified on simple physical examination and can be used to identify digital clubbing and to monitor this dynamic process objectively.1 Various imaging modalities have been used not only to evaluate clubbing but also to help identify possible clues to its development. Details of physical examination are given below.

Pathophysiology

The specific pathophysiologic mechanism of digital clubbing remains unknown. Many theories have been proposed, yet none have received widespread acceptance as a comprehensive explanation for the phenomenon of digital clubbing. As stated best by Samuel West in 1897, “Clubbing is one of those phenomena with which we are all so familiar that we appear to know more about it than we really do.”

Alterations in size and configuration of the clubbed digit result from changes in the nail bed, beginning with increased interstitial edema early in the process. As clubbing progresses, the volume of the terminal portion of the digit may increase because of an increase in the vascular connective tissue and change in quality of the vascular connective tissue, although some cases have been associated with spurs of bone on the terminal phalanx. Different pathologic processes may follow different pathways to a common end. Many studies have shown increased blood flow in the clubbed portion of the finger. High-resolution magnetic resonance imaging (MRI) using a contrast agent showed nail bed hypervascularization as linked with clubbed nails. Most researchers agree that this results from an increase in distal digital vasodilation, the cause of which is unknown. Also unknown is the exact mechanism by which increased blood flow results in changes in the vascular connective tissue under the nail bed. Whether the vasodilation results from a circulating or local vasodilator, neural mechanism, response to hypoxemia, genetic predisposition, or a combination of these or other mediators is not agreed on currently.

Evidence that favors the presence of a circulating vasodilator derives from the association of clubbing with cyanotic congenital heart disease. Many potential vasodilators, which usually are inactivated as blood passes through the lungs, bypass the inactivation process in patients with right-to-left shunts. Patients with tetralogy of Fallot (TOF) with substantial right-to-left shunting have a high incidence of clubbing. After surgical correction eliminates the right-to-left shunt, the clubbing improves. Also previously observed is clubbing confined to the feet in patients with late untreated patent ductus arteriosus (PDA) in whom blood from the pulmonary artery bypasses the lungs and is shunted into the descending aorta. In the absence of a shunt, the circulating vasodilator may be produced by the lung tissue, or, possibly, it passes through the pulmonary circulation without getting inactivated. Proposed vasodilatory factors include ferritin, prostaglandins, bradykinin, adenine nucleotides, and 5-hydroxytryptamine.

A neural mechanism has been proposed with particular consideration of the vagal system. An increased incidence of digital clubbing has been associated with the pathology and disease of vagally innervated organs. Furthermore, regression of clubbing after vagotomy has been reported. Although some factor related to the vagal system is a possible contributor to the development of clubbing, especially clubbing occurring with hypertrophic osteoarthropathy (HOA), the hypothesis of a neural mechanism has decreased in popularity because of the lack of evidence of clubbing in neurologic disorders and the presence of clubbing in diseases of organs not innervated by the vagal system.

Hypoxia has been proposed as an alternative explanation for clubbing in cyanotic heart disease and pulmonary diseases. An increase in hypoxia may activate local vasodilators, consequently increasing blood flow to the distal portion of the digits; however, in most cases, hypoxia is absent in the presence of clubbing, and many diseases with noted hypoxia are not associated with clubbing.

Genetic inheritance and predisposition also may play a role in digital clubbing. Hereditary clubbing is observed in two forms, including idiopathic hereditary clubbing and clubbing associated with PDP. The two forms are believed to be separate entities. Both demonstrate autosomal dominant inheritance with incomplete penetrance.

More recently, platelet-derived growth factor released from fragments of platelet clumps or megakaryocytes has been proposed as the mechanism by which digital clubbing occurs. The fragments are large enough to lodge in the vascular beds of the fingertips, and, subsequently, they release platelet-derived growth factor. This factor has been shown to have general growth-promoting activity and causes increased capillary permeability and connective tissue hypertrophy.2

Epidemiology

Physical Examination

Clubbing is a clinical finding characterized by bulbous fusiform enlargement of the distal portion of a digit (Fig. 1).

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Fig. 1 Comparison of normal and clubbed fingernails: (A) Normal finger viewed from above and in profile, and the changes occurring in established clubbing, viewed from above and in profile. (B) The finger on the left demonstrates normal profile (ABC) and normal hyponychial (ABD) nail fold angles. The clubbed finger on the right shows increased profile and hyponychial nail fold angles. (C) Distal phalangeal finger depth (DPD)-interphalangeal finger depth (IPD) represents the phalangeal depth ratio. In normal fingers, the IPD is greater than the DPD. In clubbing, this relationship is reversed. (D) Demonstrating the Schamroth sign.

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Fig. 1 Comparison of normal and clubbed fingernails: (A) Normal finger viewed from above and in profile, and the changes occurring in established clubbing, viewed from above and in profile. (B) The finger on the left demonstrates normal profile (ABC) and normal hyponychial (ABD) nail fold angles. The clubbed finger on the right shows increased profile and hyponychial nail fold angles. (C) Distal phalangeal finger depth (DPD)-interphalangeal finger depth (IPD) represents the phalangeal depth ratio. In normal fingers, the IPD is greater than the DPD. In clubbing, this relationship is reversed. (D) Demonstrating the Schamroth sign.

When the profile of the distal digit is viewed, the angle made by the proximal nail fold and nail plate (Lovibond angle) typically is less than or equal to 160 degrees.4 In clubbing, the angle flattens out and increases as the severity of the clubbing increases. If the angle is greater than 180 degrees, definitive clubbing exists. An angle between 160 and 180 degrees falls in a gray area and may indicate early stages of clubbing or a pseudoclubbing phenomenon.

Individuals without clubbing display a diamond-shaped window at the base of the nail beds when the dorsums of two fingers from the opposite hands are opposed. The distal angle between the two opposed nails should be minimal. In individuals with digital clubbing, the diamond window is obliterated and the distal angle between the nails increases with increasing severity of clubbing.

The nail moves more freely in patients with clubbing; therefore, the examiner may note a spongy sensation as the nail is pressed toward the nail plate. The sponginess results from increased fibrovascular tissue between the nail and the phalanx. The skin at the base of the nail may be smooth and shiny.

Obliteration in clubbed fingers of the diamond-shaped window normally produced when the dorsal surfaces of the corresponding finger of each hand are opposed (Schamroth sign) may useful for the identification of clubbing.

Grading of Clubbing

• Grade 1: Nail bed fluctuation.

• Grade 2: Obliteration of the Lovibond angle.

• Grade 3: Parrot beaking.

• Grade 4: Hypertrophic osteo-arthropathy (HOA).

Causes

Clubbing can be idiopathic or secondary to many underlying pathologies in various organ systems.5

Causes of idiopathic or primary clubbing include PDP, familial clubbing, and HOA.

Causes of secondary clubbing include the following:6

• Pulmonary disease: Lung cancer, cystic fibrosis, interstitial lung disease, idiopathic pulmonary fibrosis, sarcoidosis, lipoid pneumonia, empyema, pleural mesothelioma, pulmonary artery sarcoma, cryptogenic fibrosing alveolitis, lung hydatid cysts, surfactant protein C p, V39L mutation,7 and pulmonary metastases. In emphysema, secondary polycythemia is generally present due to severe pulmonary insufficiency producing cyanosis and clubbing of the fingers may occur.8

• Cardiac causes are detailed in the following text.9

• Gastrointestinal disease: Ulcerative colitis, Crohn's disease, primary biliary cirrhosis, cirrhosis of the liver, hepatopulmonary syndrome, leiomyoma of the esophagus, achalasia, Whipple' disease, and peptic ulceration of the esophagus.10

• Skin disease: PDP, Bureau-Barrière-Thomas syndrome, Fischer's syndrome, palmoplantar keratoderma, and Volavsek's syndrome.11

• Malignancies: Thyroid cancer, thymus cancer, Hodgkin's disease,12 and disseminated chronic myeloid leukemia (POEMS [polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes] syndrome. In lung malignancy, skeletal–connective tissue syndromes include clubbing in 30% of cases (usually non–small-cell carcinomas) and hypertrophic pulmonary osteoarthropathy in 1 to 10% of cases (usually adenocarcinomas), with periostitis and clubbing causing pain, tenderness, and swelling over the affected bones and a positive bone scan.13

• Miscellaneous conditions: Acromegaly, thyroid acropachy, pregnancy, an unusual complication of severe secondary hyperparathyroidism, sickle cell disease, and hypoxemia possibly related to long-term smoking of cannabis.14 Thyroid acropachy refers to a form of clubbing found in less than 1% of patients with Graves' disease. It is so strongly associated with thyroid dermopathy that an alternative cause of clubbing should be sought in a Graves' patient without coincident skin and orbital involvement.15

HOA in adults is often a sign of internal cancer. Other stigmata may also be evident, such as acquired keratoderma taking on a yellow velvety appearance with accentuation of dermatoglyphic lines.

As a paraneoplastic syndrome, it is most commonly associated with non–small-cell lung cancer, although it may occur with metastatic melanoma and other cancers. Hypertrophic pulmonary osteoarthropathy is evident in 1 to 5 % of all patients with non–small-cell lung cancer.

Among hemodialysis patients with end-stage renal disease, the finding of clubbing was linked with the calcium-phosphorus product.

Diagnostic Considerations

HOA is a syndrome defined by chronic proliferative periostitis of the long bones, digital clubbing, and joint swelling. HOA is characterized by clubbing of digits and, in more advanced stages, by periosteal new bone formation and synovial effusions.16 HOA occurs in primary or familial form and usually begins in childhood. The secondary form of HOA is associated with intrathoracic malignancies, suppurative lung disease, congenital heart disease, and a variety of other disorders, and is more common in adults. Clubbing is almost always a feature of HOA but can occur as an isolated manifestation. The presence of clubbing in isolation is generally considered to represent either an early stage or an element in the spectrum of HOA. The presence of only clubbing in a patient usually has the same clinical significance as HOA.17

Primary or familial HOA, also referred to as PDP or Touraine-Solente-Golé syndrome, usually begins insidiously at puberty. In a smaller number of patients, the onset is in the first year of life. The disorder is inherited as an autosomal dominant trait with variable expression and is nine times more common in boys than in girls. Approximately one-third of patients have a family history of primary HOA.

Primary HOA is characterized by clubbing, periostitis, and unusual skin features. A small number of patients with this syndrome do not express clubbing. The skin changes and periostitis are prominent features of this syndrome. The skin becomes thickened and coarse. Deep nasolabial folds develop, and the forehead may become furrowed. Patients may have heavy-appearing eyelids and ptosis. The skin is often greasy, and there may be excessive sweating of the hands and feet. Patients may also experience acne vulgaris, seborrhea, and folliculitis. In a few patients, the skin over the scalp becomes very thick and corrugated, a feature that has been descriptively termed cutis verticis gyrata. The distal extremities, particularly the legs, become thickened owing to proliferation of new bone and soft tissue; when the process is extensive, the distal lower extremities resemble those of an elephant. The periostitis is usually not painful, as it may be in secondary HOA. Clubbing of the fingers may be extensive, producing large, bulbous deformities, and clumsiness. Clubbing also affects the toes. Patients may experience articular and periarticular pain, especially in the ankles and knees, and joint motion may be mildly restricted owing to periarticular bone overgrowth. Noninflammatory effusions occur in the wrists, knees, and ankles. Synovial hypertrophy is not found. Associated abnormalities observed in patients with primary HOA include hypertrophic gastropathy, bone marrow failure, female escutcheon, gynecomastia, and cranial suture defects. In patients with primary HOA, the symptoms disappear when adulthood is reached.18

HOA secondary to an underlying disease occurs more frequently than primary HOA. It accompanies a variety of disorders and may precede clinical features of the associated disorder by months. Clubbing is more frequent than the full syndrome of HOA in patients with associated illnesses. Because clubbing evolves over months and is usually asymptomatic, it is often recognized first by the physician and not the patient. Patients may experience a burning sensation in their fingertips. Clubbing is characterized by widening of the fingertips, enlargement of the distal volar pad, convexity of the nail contour, and the loss of the normal 15-degree angle between the proximal nail and cuticle. The thickness of the digit at the base of the nail is greater than that at the distal interphalangeal joint. An objective measurement of finger clubbing can be made by determining the diameter at the base of the nail and at the distal interphalangeal joint of all 10 digits. Clubbing is present when the sum of the individual digit ratios is greater than 10. At the bedside, clubbing can be appreciated by having the patient place the dorsal surface of the distal phalanges of the fourth fingers together with the nails of the fourth fingers opposing each other. Normally, an open area is visible between the bases of the opposing fingernails. When clubbing is present, this open space is no longer visible. The base of the nail feels spongy when compressed, and the nail can be easily rocked on its bed. Marked periungual erythema is usually present. When clubbing is advanced, the finger may have a drumstick appearance, and the distal interphalangeal joint can be hyperextended. Periosteal involvement in the distal extremities may produce a burning or deep-seated aching pain. The pain can be quite incapacitating and is aggravated by dependency and relieved by elevation of the affected limbs. The overlying soft tissue may be swollen and the skin slightly erythematous. Pressure applied over the distal forearms and legs may be quite painful.

Patients may also experience joint pain, most often in the ankles, wrists, and knees. Joint effusions may be present; usually they are small and noninflammatory. The small joints of the hands are rarely affected. Severe joint or bone pain may be the presenting symptom of an underlying lung malignancy and may precede the appearance of clubbing. In addition, the progression of HOA tends to be more rapid when associated with malignancies, most notably bronchogenic carcinoma. Unlike primary HOA, excessive sweating and oiliness of the skin and thickening of the facial skin are uncommon in secondary HOA.

HOA occurs in 5 to 10% of patients with intrathoracic malignancies, the most common being bronchogenic carcinoma and pleural tumors (Table 1). Lung metastases infrequently cause HOA. HOA is also seen in patients with intrathoracic infections, including lung abscesses, empyema, bronchiectasis, chronic obstructive lung disease, and, uncommonly, pulmonary tuberculosis. HOA may also accompany chronic interstitial pneumonitis, sarcoidosis, and cystic fibrosis. In the latter, clubbing is more common than the full syndrome of HOA. Other causes of clubbing include congenital heart disease with right-to-left shunts; bacterial endocarditis; Crohn's disease; ulcerative colitis, sprue; and neoplasms of the esophagus, liver, and small and large bowel. In patients with congenital heart disease with right-to-left shunts, clubbing alone occurs more often than the full syndrome of HOA.

Unilateral clubbing has been found in association with aneurysms of major extremity arteries, with infected arterial grafts, and with arteriovenous fistulas of the brachial vessels. Clubbing of the toes but not fingers has been associated with an infected abdominal aortic aneurysm and PDA. Clubbing of a single digit may follow trauma and has been reported in tophaceous gout and sarcoidosis. While clubbing occurs more commonly than the full syndrome in most diseases, periostitis in the absence of clubbing has been observed in the affected limb of patients with infected arterial grafts.

Hyperthyroidism (Graves' disease), treated or untreated, is occasionally associated with clubbing and periostitis of the bones of the hands and feet. This condition is referred to as thyroid acropachy. Periostitis is asymptomatic and occurs in the midshaft and diaphyseal portion of the metacarpal and phalangeal bones. The long bones of the extremities are seldom affected. Elevated levels of long-acting thyroid stimulator are found in the serum of these patients.

In some instances it is occupational, for example in jackhammer operators.

Pseudoclubbing is defined as an over curvature of the nails in both the longitudinal and transverse axes, with preservation of a normal Lovibond angle.

Cardiac Causes of Clubbing

In cyanotic congenital heart diseases, clubbing occurs as sequelae of hypoxemia. Clubbing of the fingers and toes occurs after 3 months of age and is proportional to the level of cyanosis. Clubbing implies the presence of central shunting, although it has also been described with endocarditis.19

Cyanosis and Clubbing

Usually central cyanosis and clubbing go hand in hand. If long-standing cyanosis is present without clubbing, suspect circulating methemoglobin and by even smaller quantities of sulfhemoglobin. In both these conditions, the arterial partial pressure of oxygen (PaO₂) remains normal. Peripheral cyanosis or acutely developing central cyanosis is not associated with clubbed digits.

Symmetric Cyanosis and Clubbing

Equal cyanosis and clubbing of hands and feet caused by transposition of the great vessels and a VSD without PDA (Fig. 2).

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Fig. 2 Symmetric Cyanosis.

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Fig. 2 Symmetric Cyanosis.

Asymmetric Cyanosis and Clubbing

Differential cyanosis provides information about anatomy.36 Cyanosis and clubbing of the toes associated with pink fingernails of the right hand and cyanosis and clubbing of the left hand are caused by a PDA with normally related great vessels and a reversed shunt as a result of pulmonary hypertension, with the PDA delivering cyanotic blood to the left arm and lower extremities. The same color pattern results from interruption of the aortic arch and a PDA delivering desaturated blood to the legs. However, if the right subclavian artery arises proximal to the aortic obstruction, the right hand can be pink and the left hand cyanotic. When an anomalous right subclavian artery originates from the descending aorta, both hands are cyanotic. Cyanosis of the fingers greater than in the toes indicates complete transposition of the great vessels with preductal Coarctation or complete interruption of the aortic arch, pulmonary hypertension, and a reverse shunt through a PDA, (with shunting of the more oxygenated pulmonary artery blood as seen transposition physiology) delivers blood with higher saturation to the lower extremities.

In Eisenmenger's VSD with PDA, when shunt reversal is there as both levels, the patient can have both upper and lower limb cyanosis and clubbing, instead of differential clubbing due to PDA. Still there may be differential saturations in upper and lower limbs along with low basal oxygen saturation. For example in Fig. 3, this patient has Eisenmenger's VSD with PDA with shunt reversal at both levels. The patient developed diffuse clubbing with more desaturated blood to lower limb (SO₂ = 62%) than upper limb (SO₂ = 78%) (Personal communication).

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Fig. 3 Clubbing of both upper and lower limbs with more clubbing of lower limbs. This patient has Eisenmenger's VSD with PDA with shunt reversal at both levels. PDA, patent ductus arteriosus; VSD, ventricular septal defect.

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Fig. 3 Clubbing of both upper and lower limbs with more clubbing of lower limbs. This patient has Eisenmenger's VSD with PDA with shunt reversal at both levels. PDA, patent ductus arteriosus; VSD, ventricular septal defect.

Imaging Studies

Histologic Findings

Microscopically, the collagen fibrils and cells are separated by a distance greater than that seen in histologically normal specimens. This increased separation results in a less dense nail bed matrix. Primitive fibroblasts are seen with large nuclei, basophilic cytoplasm, and long reticular processes. Increased and scattered extravascular lymphocytes and, less often, a moderately increased number of tissue eosinophils also are noted in the nail beds of some specimens. The periosteum of the nail bed may be thickened with increased vascular penetration.

Eventually, increased collagen is laid down in all types of chronic clubbing. The mat of collagen fibers may be abnormally thick and dense. The walls of the vascular components increase in thickness and are encased in a thick fibrous sheet. At this stage of clubbing, the histologic and morphologic changes probably are irreversible.

Prognosis

Since clubbing of the fingers is a clinical finding, it is not an independent cause of mortality; however, mortality associated with underlying pathology in patients with secondary clubbing widely varies.

Morbidity is minimal and is typically associated with the cosmetic appearance of clubbed digits.

Treatment of the underlying pathologic condition may decrease the clubbing or, potentially, reverse it if performed early enough. Once substantial chronic tissue changes, including increased collagen deposition, have occurred, reversal is unlikely. Prognosis of the underlying disease should be determined on an individual basis.