44 ClubbingSTEPHEN J . McPHEE

Definition

Clubbing is a physical sign characterized by bulbous enlarge-ment of the ends of one or more fingers or toes (Figure44.1) . Proliferation and edema of connective tissue resultin loss of the normal angle between the skin and nail plateand excessive sponginess of the nail base . Clubbing is usuallyacquired and is associated with certain cardiopulmonaryand gastrointestinal disorders, but may occur in congenitalor familial forms . Acropachy is an alternative term for club-bing. Acquired clubbing is often reversible when the asso-ciated condition is treated successfully .

Hypertrophic osteoarthropathy is an advanced stage of club-bing where there is painful periosteal proliferation of longbones such as the radius, ulna, or tibia . The periostitis isoften associated with mild fever and arthralgia or joint ef-fusion. Peripheral neurovascular disease with cyanosis, ex-cessive sweating (hyperhidrosis), paresthesias, and muscularweakness can also occur .

Pachydermoperiostosis is a syndrome that combines hyper-trophic osteoarthropathy and acromegalic features . Patientswith this disorder have cylindrical thickening of the limbsdue to periostosis and skin changes . The skin changes in-clude marked thickening and oiliness of the skin of thehands, forearms, and legs ; accentuation of facial folds ; hy-perhidrosis of the hands and feet ; and reduplication andfurrowing of skin over the scalp (called cutis verticis gyrata,or "bulldog scalp"). There may also be macroglossia . Thehereditary form of pachydermoperiostosis may be inheritedas an autosomal dominant trait with incomplete penetranceand is most severe in males . It usually has its onset in thelate teens . The acquired form is not associated with a familyhistory of the disorder, usually occurs in older men, and isassociated with coexisting chronic cardiopulmonary or gas-trointestinal neoplasm or infection .

Figure 44 .1Clubbing of the fingers of one hand .

Technique

Clubbing

Clubbing is usually painless and bilateral . The patient maybe unaware of the gradual enlargement of fingertips or toesuntil it is brought to his or her attention . Patients with he-reditary clubbing may report a family history of clubbingor a long duration of clubbing without any symptoms orsigns to suggest an underlying illness . In acute cases, themore rapid onset or mild associated discomfort may drawattention to the deformity . It is important to detect earlyclubbing because clubbing can be the first clue to a seriousunderlying disorder that, if treated early, may be curable .

Clubbing usually develops first in the thumb and fore-finger, and occurs in the other fingers later. It may bedifficult to recognize unless the examiner observes the hands(and feet) carefully . Two signs are characteristic of earlyclubbing : the "floating nail" sign and the "profile" sign .

The "floating nail" sign is easily demonstrated (Figure44.2) . Normally, the root of the nail plate lies snugly againstthe bone of the distal phalanx ; pressure on the root pro-duces no movement . With clubbing, the root is separatedfrom bone by connective tissue and edema ; pressure uponthe nail plate moves it toward the bone . The base of thenail becomes resilient and springy, and the nail feels as ifit is floating on a cushion . As clubbing progresses, the nailbecomes loosely attached, and the free edge of the nail platemay become visible or palpable as a horizontal ridge overthe dorsal aspect of the finger .

The "profile" sign is illustrated in Figures 44 .2 and 44.3 .Normally, the angle between the nail plate and the skinoverlying the proximal part of the distal phalanx is about160 degrees or less. With clubbing, proliferation of tissueunder the nail plate causes this angle to increase to morethan 160 degrees . In fact, the angle may be entirely lost andthe nail plate and skin lie in a straight line (180-degree

Figure 44 .2The normal and clubbed fingertip. The "floating nail" sign is dem-onstrated by applying pressure at the point indicated as the root ofthe nail plate . Normally, pressure there produces no movement .With clubbing, there is movement toward the bone . The "profile"sign is produced by an increased angle between the nail plate andthe skin overlying the proximal part of the distal phalanx . Nor-mally, the angle is about 160 degrees or less . As clubbing progresses,the angle exceeds 180 degrees .

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Figure 44.3The clubbed fingertip in profile .

angle). As clubbing progresses, the angle exceeds 180 de-grees. Eventually, the profile of the fingertip becomes bul-bous .

Obliteration of the angle between the nail and the nailbedis the first sign of clubbing and its most constant feature ;indeed, many require it for the diagnosis . Because it can beeasily detected and precisely defined, the examiner shouldrely on this sign when uncertain if a patient's fingers aretruly clubbed .

Early clubbing must be distinguished from several otherabnormalities of the fingertip . These include : (1) increasednail curvature, a normal finding in many adults (especiallyblacks) ; (2) chronic paronychiae, in which the soft tissue atthe base of the nail is inflammed and swollen ; and (3) felonsor abscesses of the terminal pulp space, in which there isswelling over the palmar surface of the fingertip . In noneof these conditions, however, is the fundamental angle be-tween nail and terminal phalanx altered . A simple maneu-ver (described by Schamroth) readily differentiates trueclubbing from these pseudo-clubbing conditions . The ex-aminer asks the patient to hold the two thumbs back to backwith the two fingertips and interphalangeal joints aligned .Because the base angle is unaltered in these conditions, anelongated, diamond-shaped area of empty space is appar-ent. In true clubbing, this empty space is lost . (Schamroth,while himself ill with subacute bacterial endocarditis, notedthis finding as one of the earliest signs of clubbing ; he alsoreported that the window of empty space reappeared 2months after his endocarditis had been treated successfully .)

Increased nail curvature, when it occurs in clubbing, ap-pears later than either proliferation of tissue at the nail baseor loss of the normal angle between distal phalanx and nail .Though increased nail curvature is not specific to clubbing,when it occurs, the entire nail assumes an abnormally con-vex appearance (often described as the "watch-crystal" nail) .Later still, when the entire distal phalanx is enlarged andbulbous, it may resemble a drumstick .

Clubbing of the toes is more difficult to recognize be-cause the tips of the toes may normally appear somewhatbulbous . True clubbing is usually easiest to recognize in thegreat toe. In addition, the examiner may learn to recognizeit because clubbing of the toes is frequently found in patientswith clubbing of the fingers . Finally, in acute cases, thepatient may have noted either mild discomfort or changedappearance of the digits .

Hypertrophic Osteoarthropathy

Hypertrophic osteoarthropathy should always be soughtwhen clubbing is found . The symptomatic patient with hy-pertrophic osteoarthropathy will complain of severe, burn-ing, deep pain over the distal extremities, especially of thelegs, that is worsened at night and on dependency . In earlycases, the examiner may note warmth, reddening, or brawnyedema of the skin over the distal long bones (particularlyover the shins). In acute or severe cases, there may be ex-quisite tenderness of the feet and legs and the hands andforearms, and tenderness and effusions of the adjacent joints(the ankles, knees, wrists, and fingers) . The examiner mayelicit tenderness over bony prominences by simply pressingor by encircling the limb (e .g ., the wrist) with his own fingerslike a bracelet and gently squeezing it . Later, autonomicchanges such as flushing, sweating, or blanching (Raynaud'sphenomenon) may be noted in the affected hands and feet .

Pachydermoperiostosis

Patients with pachydermoperiostosis most often complainabout their changing appearance or the excessive perspi-ration, especially of the hands and feet . During the activephase of their disorder, they may have mild bone pain orarthralgia . Later, they may complain of clumsiness of theirfingers, ptosis from thickening of the skin over their eyelids,or facial palsy from thickening of the skull. On examinationof the skeleton, there is clubbing of the fingers and toes,accompanied by "spadelike" or "pawlike" enlargement ofthe hands and feet; joint effusions may be present. The skinchanges include excessive sweating, generalized thickening(called pachyderma) and redundancy, especially over theforehead and scalp, leading to characteristic "bulldog" fur-rowing (cutis verticil gyrata) and leonine facies, sometimesmistaken for leprosy . The cylindrical thickening of the ex-tremities resulting from a combination of bony enlargementand thickening of the skin is often the most impressivephysical finding and may suggest the diagnosis of acro-megaly .

Further Evaluation

In all three conditions (i .e ., clubbing, hypertrophic osteoar-thropathy, and pachydermoperiostosis), the physician shouldspecifically examine for findings of associated illness, in-cluding wheezes, rales, pleural effusion, supraclavicular ad-enopathy, cardiac murmurs, Roth spots, peripheral stigmataof endocarditis, splenomegaly, jaundice, vascular angio-mata, palmar erythema, hepatomegaly, abdominal mass(suggesting regional enteritis), thyromegaly, and ophthal-mopathy .

In addition, because clubbing may be a manifestation ofeither hypertrophic osteoarthropathy or pachydermoperio-stosis, the clinician may want to obtain x-rays of the distalextremities . In early clubbing, x-rays will be normal exceptfor increased soft tissue. In the later stages, there may befraying of the edges of the distal phalanx, followed by grad-ual resorption of the bone (acro-osteolysis) . X-rays of pa-tients with hypertrophic osteoarthropathy may showsymmetrical, irregular periosteal proliferation, calcificationand new bone formation (periostitis) over the distal armsand legs, or acro-osteolysis of the distal phalanges of fingersand toes. The finding that 99m-technetium pyrophosphate

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bone scans are more sensitive than plain x-rays in detectingearly periostitis can be helpful in difficult cases . In advancedcases of osteoarthropathy, and in pachydermoperiostosis,x-rays may show extreme degrees of periostitis in almostany bone, although the skull, vertebrae, and articular sur-faces are usually spared .

Synovial fluid obtained by arthrocentesis in patients withpainful joint effusions in osteoarthropathy are usually "non-inflammatory," with a leukocyte count less than 2000/mm 3and with 0 to 50% neutrophils . Interestingly, this fluid tendsto clot spontaneously after aspiration, a finding usually re-served for inflammatory effusions .

Further radiologic or laboratory studies, such as a chestx-ray, small bowel series, thyroid function panel, or bloodcultures, may be performed to examine for underlying ill-ness. The patient's symptoms and signs will indicate theappropriate procedures .

Basic Science

Although many explanatory theories have been put for-ward, the etiology of clubbing is unknown . Flavell (1956)quotes West, who said in 1907 that "clubbing is one of thosephenomena with which we are all so familiar that we appearto know more about it than we really do ."

Shneerson (1981) reviews the four most likely mecha-nisms underlying clubbing. They include a circulating va-sodilator, tissue hypoxia, a neurocirculatory reflex, andgenetic factors . For acquired clubbing, the most likely mech-anism postulates a neurocirculatory reflex, leading to in-creased blood flow through multiple arteriovenous shuntsin the distal phalanges . Increased blood flow then leads totissue hypertrophy and hyperplasia on a nutritional basis .The evidence for this mechanism is threefold : (1) clubbingmay resolve after vagotomy ; (2) disturbances of the vas-culature such as arteriovenous fistulae and aneurysms areassociated with its development ; and (3) Racoceanu (1971)and others have demonstrated increased blood flow to dig-itial capillaries in acquired clubbing .

Flavell (1956) first proposed the neurocirculatory reflextheory to explain hypertrophic osteoarthropathy, after heobserved that severing the vagus nerve could reverse it evenwhen the underlying lung cancer was unresectable . Ac-cording to this theory, there is a reflex in which afferentimpulses travel by the vagus nerve from the inciting focus(such as a lung tumor) to the central nervous system . Theefferent limb of the proposed reflex is unknown, but pre-sumably some humoral substance or neural impulse me-diates the vascular changes, leading to hypertrophy of thefibroconnective tissues . Others have supported such amechanism by observations that the visceral organs in whichassociated diseases occur are all innervated by the glosso-pharyngeal or vagus nerves .

Strong support for this theory has also come from a studyby Gold and colleagues (1979) . They studied a unique caseof unilateral clubbing secondary to a posttraumatic aneu-rysm of the ulnar artery, which resolved after resection ofthe aneurysm . Using the contralateral hand of the otherwisehealthy patient, they conducted detailed studies of the mi-crocirculation by Doppler flow recordings, differential pulsepressure measurements, angiography, measurements of re-active hyperemia, and differential capillary blood gas de-terminations . They interpreted their findings of increasedblood flow, decreased peripheral resistance, and increasedoxygenation to support the neurocirculatory reflex mech-

anism. They postulated that the efferent limb of the reflexwas cholinergic fibers of the autonomic sympathetic inner-vation of digital arteriovenous shunts .

However, different mechanisms may cause acquired andhereditary clubbing . Some workers have found that digitalcapillary blood flow, measured by washout of krypton-85solution, is increased in acquired clubbing but normal inhereditary clubbing. An alternative explanation for thisfinding may be that in hereditary clubbing the conditionhas been studied only after the condition has stopped pro-gressing; the physiologic findings might be similar in theactive phase .

There may be different pathogeneses of acquired club-bing and osteoarthropathy. Each may occur without theother . Some conditions frequently associated with clubbingare seldom seen with osteoarthropathy, and vice versa . Left-to-right pulmonary arteriovenous shunting may be impor-tant in the pathogenesis of osteoarthropathy in some patients,such as those with chronic liver disease, but cannot explainothers, such as those with marked right-to-left shunts . Over-all, however, both the pathology and physiology in limbsaffected by osteoarthropathy resemble that of the digitsaffected by clubbing .

Study of synovial tissue from patients with hypertrophicpulmonary osteoarthropathy has shown evidence of micro-vascular injury, perhaps related to electron-dense depositsfound in the synovial vessel walls . These dense deposits donot stain for immunoglobulins or complement, however,and may simply represent proteins such as fibrinogen thathave leaked through the damaged blood vessel walls .

The pathogenesis of pachydermoperiostosis seems quitedifferent. Blood flow in the limbs as measured by pleth-ysmography and arteriovenous oxygen differences is nor-mal, capillaroscopy shows few vessels, and angiograms showslowed flow with segmental arterial narrowing . Various hu-moral agents such as hormones have been proposed to ex-plain its pathogenesis, but there is little evidence to supportsuch a mechanism. For example, despite the acromegaloidfeatures of affected patients, there has been no evidence ofectopic secretion of excessive amounts of growth hormone .

Clinical Significance

The earliest known description of clubbing is that of Hip-pocrates, who noted in the fifth century B.C . its associationwith chronic empyema . He wrote: "The nails of the handare bent; the fingers are hot especially in their extremities ."

Clubbing and hypertrophic osteoarthropathy are im-portant to recognize because they are usually associated withserious underlying disease . In addition, because clubbingmay precede any other evidence of the underlying disorder,it may serve as the only clue to an otherwise silent lesion .It may, for example, allow early recognition and surgicalcure of an otherwise asymptomatic lung tumor .

Review of the literature indicates that between 75 and80% of cases are associated with chronic pulmonary dis-eases; 10 to 15% are associated with cardiovascular diseases ;5 to 10% with chronic hepatic and gastrointestinal disor-ders ; and 5 to 10% with miscellaneous disorders .

Pulmonary disease is the most common cause (Table 44 .1) .Primary or secondary malignancy of the bronchus or lung,as well as tumors of the pleura, mediastinum, thymus, andchest wall, are perhaps the most worrisome associations . Buta variety of chronic pulmonary infections, including lungabscess, chronic empyema, pneumoconiosis, chronic pneu-

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monitis, cystic fibrosis, emphysema with chronic suppura-tion, actinomycosis, and bronchiectasis, can also producethe characteristic picture . Clubbing is said to be uncommonin uncomplicated pulmonary tuberculosis, but may occurin up to 25% of cases with supervening bronchiectasis orchronic cavitation . More rarely, it has been described inpatients with chest deformities, aortic aneurysm withcompression of lung, and neurogenic tumors of thediaphragm .

Cardiovascular diseases rank second among the causes ofclubbing and hypertrophic osteoarthropathy (Table 44 .1) .Associated diseases include cyanotic congenital heart dis-eases (diseases with right-to-left shunts), subacute bacterialendocarditis, chronic congestive heart failure, cor pulmo-nale, cardiac tumors, pulmonary arteriovenous fistulas, andsecondary polycythemia .

Chronic hepatic and gastrointestinal disorders associated withclubbing include primary and secondary biliary cirrhosis,amebic liver abscess, hepatic amyloidosis, ascariasis, malaria,intestinal tuberculosis, chronic amebic dysentery, ulcerativecolitis, regional enteritis, sprue, intestinal polyposis, abdom-inal lymphoma, and carcinomas of the nasopharynx, esoph-agus, stomach, and colon (Table 44 .1) .

Miscellaneous associations include thyrotoxicosis (thyroidacropachy), hyperparathyroidism, pregnancy, chronic os-teomyelitis with amyloidosis, chronic pyelonephritis, pseu-dohypertrophic muscular dystrophy, hemoglobinopathies,chronic mountain sickness (Monge's disease), syringomye-lia, renal carcinoma, chronic myelocytic leukemia, and ex-posure to toxins such as arsenic, mercury, silica, beryllium,phosphorus, and alcohol (Table 44 .1) .

Asymmetrical clubbing usually indicates impaired re-gional blood flow caused by localized vascular disease . Uni-lateral clubbing in the upper extremity may be due toanomalies of the aortic arch, aortic or subclavian arteryaneurysm, pulmonary hypertension with patent ductus ar-teriosus, and brachial arteriovenous aneurysm or fistula .Rarely, it has been described with recurrent dislocation ofthe shoulder and superior sulcus (Pancoast) tumor. Club-bing of toes but not fingers suggests coarctation of the aorta .Unidigital clubbing is seen following median nerve injuryand, rarely, with sarcoidosis. Recurrent clubbing may occurduring pregnancy in otherwise healthy women . Familialclubbing is of no clinical import (unless associated withpachydermoperiostosis) .

Table 44.1Conditions Associated with Clubbing

I. Symmetrical Clubbing Esophageal carcinomaPulmonary disease Gastric carcinomaNeoplasm Colonic carcinomaBronchogenic carcinoma MiscellaneousPleural mesothelioma Endocrine conditionsThymoma HyperthyroidismMetastatic carcinoma Hyperparathyroidism

Chronic infection PregnancyLung abscess Chronic infectionsChronic empyema Chronic osteomyelitis with amyloidosisPneumoconiosis Chronic pyelonephritisChronic pneumonitis Congenital disordersCystic fibrosis Muscular dystrophyEmphysema with chronic suppuration HemoglobinopathiesActinomycosis Idiopathic disordersBronchiectasis Chronic mountain sickness

Cardiovascular disease SyringomyeliaCyanotic congenital heart disease NeoplasmsSubacute bacterial endocarditis Renal carcinomaCor pulmonale Chronic myelocytic leukemiaSecondary polycythemia Toxin exposureChronic congestive heart failure ArsenicCardiac tumors MercuryPulmonary arteriovenous fistula SilicaArterial graft infection Beryllium

Hepatic and gastrointestinal disease PhosphorusHepatic Alcohol

Cirrhosis (all types) Chronic laxative abuseAmebic abscess FamilialAmyloidosis

GastrointestinalChronic infection

AscariasisII. Asymmetrical Clubbing

UnilateralMalaria Anomalous aortic archIntestinal tuberculosis Aortic or subclavian artery aneurysmChronic amebic dysentery Pulmonary hypertension with patent ductus arteriosus

Chronic inflammation Brachial arteriovenous aneurysm or fistulaUlcerative colitis Recurrent shoulder dislocationRegional enteritis Superior sulcus (Pancoast) tumorSprue Unidigital

Neoplasm Median nerve injuryIntestinal polyposis SarcoidosisAbdominal lymphoma Clubbing of toes without fingersNasopharyngeal carcinoma Coarctation of aorta

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