Digital Clubbing
2013; Lippincott Williams & Wilkins; Volume: 127; Issue: 19 Linguagem: Tagalog
10.1161/circulationaha.112.000163
ISSN1524-4539
Autores Tópico(s)Gastrointestinal Tumor Research and Treatment
ResumoHomeCirculationVol. 127, No. 19Digital Clubbing Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBDigital Clubbing John D. Rutherford, MB ChB, FRACP John D. RutherfordJohn D. Rutherford From the Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX. Originally published14 May 2013https://doi.org/10.1161/CIRCULATIONAHA.112.000163Circulation. 2013;127:1997–1999IntroductionA 66-year-old man presented to his cardiologist with a 3-month history of feeling tired, a 6.8 Kg weight loss, and occasional night sweats. He had a remote 17–pack-year history of smoking. Eighteen months previously, he had undergone an aortic valve replacement for symptomatic aortic valve stenosis. His examination revealed a normal temperature, a heart rate of 95 bpm, a blood pressure of 140/90 mmHg, a soft aortic ejection flow murmur without a detectable diastolic murmur, and no clinical evidence of heart failure. He was noted to have painless bilateral finger clubbing without evidence of palpable splenomegaly or peripheral embolic phenomena. His optic fundi were normal. In addition to the history of weight loss, fatigue, and occasional night sweats, the presence of finger clubbing leads one to consider its major causes.1Digital clubbing was first described by Hippocrates in 400 bc in a patient with empyema. This unique examination finding can provide an immediate clue that a serious underlying condition may exist. In 1938, Lovibond2 described the "profile" sign (Figure),3 which, if >180°, indicates true clubbing of the fingers. (The normal angle between the nail bed and the proximal nail fold is 160°.) In addition, there is periungual edema and a softening of the nail bed.2 Digital clubbing may occur alone or can be part of a syndrome of joint pain and swelling associated with periostosis of tubular bones (hypertrophic osteoarthropathy [HOA]). In 1944, Paul Dudley White said,Download figureDownload PowerPointFigure. As demonstrated, the normal hyponychial angle is ≈160°, and an angle >180° is consistent with clubbing. Reprinted with permission from The Merck Manual of Diagnosis and Therapy.3 Copyright © 2010 to 2013 by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.Clubbing of the fingers and toes associated with cyanosis is found in certain congenital cardiovascular defects (the morbus cæruleus). Clubbing without cyanosis is found in subacute bacterial endocarditis. However, it must be remembered that clubbed fingers are often found with noncardiac conditions, most commonly of all in pulmonary diseases; even ulcerative colitis may be the underlying cause, and a familial type of unknown etiology has been described.4These comments reflect the spectrum of disease of his time.The major causes to consider include the following:Pulmonary malignancy. Primary lung cancer, lymphoma, pleural mesothelioma, and secondary pulmonary malignancies can all be accompanied by clubbing. Primary lung and pleural tumors may also exhibit pulmonary HOA. In 1956, Flavell5 described 5 patients with pulmonary malignancies (some inoperable) and significant, at times incapacitating, pain and swelling of the wrists, elbows, knees, or ankles that was relieved within hours or weeks by division of the vagus nerve. Tumor resection can also abate or abolish both clubbing and the associated painful osteoarthropathy. More recently, video-assisted left truncal vagotomy provided relief within hours to a patient with inoperable lung cancer who had suffered incapacitating joint symptoms.6 Painful clubbing is more likely in patients with bronchogenic carcinoma, lung abscess, and bronchiectasis.7Chronic infection (or inflammation). Digital clubbing has classically been associated with chronic infections such as bronchiectasis, lung abscess, empyema, pulmonary tuberculosis, and infective endocarditis.8 Both inflammatory bowel disease (Crohn disease more than ulcerative colitis) and chronic liver disease have been associated with clubbing. Furthermore, clubbing has been seen with HIV and chronic parasitic infections with Trichuris trichiura (whipworm) and schistosomal colonic polyposis.Cyanotic congenital heart disease.Primary HOA. This is a rare familial condition. Homozygous individuals have chronically elevated prostaglandin E2 levels and prominent clubbing. Mutations were first reported in 2008 in the 15-hydroxy-prostaglandin dehydrogenase (HPGD) gene encoding the major prostaglandin catabolizing enzyme (prostaglandin E2).9 Heterozygotes show milder manifestations. In individuals with autosomal-recessive primary HOA, a mutation in the prostaglandin transporter SLCO2A1 has been described.10,11 In patients with liver disease treated with prostaglandins, clubbing and cortical hyperostosis resembling HOA developed and then reversed when therapy was completed.12 In patients with primary HOA, plasma levels of vascular endothelial growth factor (VEGF) are higher than in control subjects.13PathophysiologyKnowledge of the pathophysiology of clubbing is incomplete. The case report of a 24-year-old woman with reversed shunting through a patent ductus arteriosus and oxygen saturations >90% in her arms and 63% in her femoral artery with clubbing and cyanosis only of her toes (and HOA of her lower extremities) suggests that hypoxia plays a role.14 Patients with acquired clubbing have a distinctive, abnormal capillary growth pattern, with plexus formation at right angles to the normally vertically oriented capillary loops, arborized loops with branches budding from the tips, and splayed afferent and efferent limbs of the capillary loop.15 Platelet clusters aggregating in the distal vasculature of the digits may mediate the morphological changes of clubbing.16 Furthermore, human megakaryocytes within bone marrow produce and secrete VEGF in an inducible manner. VEGF delivered to sites of vascular injury by activated platelets may initiate angiogenesis.17 In normal neonates, plasma VEGF levels are elevated but within 3 months fall rapidly. In cyanotic children, VEGF levels remain elevated and are inversely related to oxygen saturation,18 and the functional capacities of circulating endothelial progenitor cells (proliferation, migration, and adhesion) are augmented.19That resection of the vagus nerve can abate or abolish both clubbing and pulmonary osteoarthropathy led to the theory that the vagus nerve may be a key signaling pathway.20 In patients with bronchogenic carcinoma and unequivocal clubbing, both VEGF and platelet-derived growth factor, which are released with platelet aggregation and are hypoxically regulated, are increased in the digits that contain platelet clusters compared with control subjects.21 In patients with lung cancer, plasma levels of VEGF are significantly higher than in control subjects,13 and VEGF is known to be a predominant angiogenic tumor growth factor.22 Removal of a pulmonary large-cell adenocarcinoma in a female patient with digital clubbing and primary HOA dramatically reduced abnormally high plasma and serum VEGF levels. Her bone pain and clubbing deformities regressed and were absent a year after surgery.23 The resected lung tumor showed 45% greater VEGF mRNA expression than normal lung.Clubbing is more prevalent with active inflammatory bowel disease, especially when macroscopic disease is confined to the area of the gut innervated by the vagus nerve24 (ie, the small and large intestine as far as the midtransverse colon).25 Mucosa with active disease shows higher spontaneous VEGF production than normal mucosa,26 and the expression of VEGF-A and its receptor, VEGFR-2, are increased in inflamed bowel.27 Thus, VEGF appears to be a promoter of angiogenesis and inflammation in bowel disease and, when overexpressed in a mouse colitis model, worsens the condition.27Most patients with end-stage chronic liver disease undergoing evaluation for transplantation have intrapulmonary shunts (especially those with Child-Pugh classification C), and they can have lower resting Pao2 levels.28 Substantial right-to-left shunting in the lungs in association with cirrhosis, cyanosis, and clubbing was described by Rodman et al,29 who later documented minor degrees of arterial desaturation and increased venous admixture attributed to intrapulmonary shunting in cirrhotic patients.30 In patients with cirrhosis, there are increased numbers of small, dilated blood vessels in the alveolar walls (especially vessels <35 µm), with some vessels just beneath the pleural surface having the appearance of spider nevi.31 In rodent studies of cirrhosis, with the progression of fibrosis, there is hepatocellular hypoxia and increased expression of VEGF and VEGF receptors, which correlate with the density of new microvessels.32 After successful liver transplantation in a cirrhotic patient with cyanosis, clubbing, oxygen desaturation, and right-to-left shunting (demonstrated by perfusion scanning), all of these abnormalities resolved.33In the pathogenesis of digital clubbing, local hypoxia, platelet activation, release of signal proteins such as VEGF, and stimulation of angiogenesis and other cellular activities are probably contributory.In our patient, routine blood tests and blood cultures were unremarkable. An echocardiogram revealed a normally functioning aortic valve without evidence of vegetations, valve regurgitation, or abscess formation. A computed tomography of the chest revealed a lung tumor near the periphery of the lung. Fine-needle biopsy of the mass led to the diagnosis of adenocarcinoma. There was no evidence of lymphadenopathy. A lobectomy was performed. Within weeks, the finger clubbing disappeared. When new-onset digital clubbing is observed in the absence of overt pathology, a screening chest computed tomography seems warranted.AcknowledgmentsDr Samuel Goldhaber invited me to write this update when he heard my interest had been stimulated by self-diagnosed clubbing. The case history bears only a faint resemblance to my condition.Sources of FundingDr Rutherford is supported by the Jonsson-Rogers Chair in Cardiology.DisclosuresNone.FootnotesCorrespondence to John D. Rutherford, MB ChB, FRACP, FACC, Division of Cardiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390–8831. E-mail [email protected]References1. Spicknall KE, Zirwas MJ, English JC. Clubbing: an update on diagnosis, differential diagnosis, pathophysiology, and clinical relevance.J Am Acad Dermatol. 2005; 52:1020–1028.CrossrefMedlineGoogle Scholar2. Lovibond J. Diagnosis of clubbed fingers.Lancet. 1938; 1:363–364.CrossrefGoogle Scholar3. The Merck Manual of Diagnosis and Therapy. Porter R, ed. Whitehouse Station, NJ: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc; 2011-2013. http://www.merckmanuals.com/professional/index.html. Accessed February 27, 2013.Google Scholar4. White PD. Heart Disease. 3rd ed. New York: The Macmillan Company; 1944.Google Scholar5. Flavell G. Reversal of pulmonary hypertrophic osteoarthropathy by vagotomy.Lancet. 1956; 270:260–262.CrossrefMedlineGoogle Scholar6. Ooi A, Saad RA, Moorjani N, Amer KM. 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Machado M, Harada G and Castro Junior G (2020) Autoimunidade como manifestação paraneoplásica, Revista Paulista de Reumatologia, 10.46833/reumatologiasp.2020.19.1.7-12:2020 jan-mar;19(1), (7-12) Riyaz A, Faiz R, Riyaz N and Roshin R (2020) Nail: A mirror to systemic diseases in children, Journal of the Pediatrics Association of India, 10.4103/jpai.jpai_26_20, 9:2, (55), . Sears S, Carr G and Bime C (2020) Acute and Chronic Respiratory Failure in Cancer Patients Oncologic Critical Care, 10.1007/978-3-319-74588-6_43, (445-475), . Kapur S and Goyal A (2019) Clubbing masquerading as a vascular malformation!, Postgraduate Medical Journal, 10.1136/postgradmedj-2019-136787, 95:1127, (514-514), Online publication date: 1-Sep-2019. Sears S, Carr G and Bime C (2019) Acute and Chronic Respiratory Failure in Cancer Patients Oncologic Critical Care, 10.1007/978-3-319-74698-2_43-1, (1-31), . Lipner S, Lawry M, Kroumpouzos G, Scher R and Ralph Daniel C (2018) Nails in Systemic Disease Scher and Daniel's Nails, 10.1007/978-3-319-65649-6_21, (343-382), . Jenkins V, Henrique de Mello Souza C, de Lorimier L and de Toledo-Piza E (2017) Squamous Cell Carcinoma of the Penis with Pulmonary Metastasis and Paraneoplastic Hypertrophic Osteopathy in a Dog, Journal of the American Animal Hospital Association, 10.5326/JAAHA-MS-6425, 53:5, (277-280), Online publication date: 1-Sep-2017. Toonstra J (2017) Afwijkingen in de vorm en structuur van de nagelplaat Voeten en nagels, 10.1007/978-90-368-1318-1_2, (14-55), . Monge E, Coolen-Allou N, Mascarel P and Gazaille V (2016) Lymphome du MALT pulmonaire et syndromes paranéoplasiques, Revue des Maladies Respiratoires, 10.1016/j.rmr.2016.02.008, 33:9, (799-803), Online publication date: 1-Nov-2016. Dubrey S, Pal S, Singh S and Karagiannis G (2016) Digital clubbing: forms, associations and pathophysiology, British Journal of Hospital Medicine, 10.12968/hmed.2016.77.7.403, 77:7, (403-408), Online publication date: 2-Jul-2016. Callemeyn J, Van Haecke P, Peetermans W and Blockmans D (2016) Clubbing and hypertrophic osteoarthropathy: insights in diagnosis, pathophysiology, and clinical significance, Acta Clinica Belgica, 10.1080/17843286.2016.1152672, 71:3, (123-130), Online publication date: 3-May-2016. Wortsman X and Alvarez S (2014) Colour Doppler ultrasound findings in the nail in cystic fibrosis, Journal of the European Academy of Dermatology and Venereology, 10.1111/jdv.12641, 30:1, (149-151), Online publication date: 1-Jan-2016. Manger B and Schett G (2014) Paraneoplastic syndromes in rheumatology, Nature Reviews Rheumatology, 10.1038/nrrheum.2014.138, 10:11, (662-670), Online publication date: 1-Nov-2014. Rutherford J (2013) Response to Letter Regarding Article, "Digital Clubbing", Circulation, 128:23, (e449-e449), Online publication date: 1-Dec-2013.De Mattia L, Rellini G and Nicolosi G (2013) Letter by De Mattia et al Regarding Article, "Digital Clubbing", Circulation, 128:23, (e448-e448), Online publication date: 1-Dec-2013. May 14, 2013Vol 127, Issue 19 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.112.000163PMID: 23671180 Originally publishedMay 14, 2013 PDF download Advertisement SubjectsDiagnostic Testing
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