Exploring the Cause of the Most Ancient Clinical Sign of Medicine: Finger Clubbing

https://doi.org/10.1016/j.semarthrit.2006.11.004Get rights and content

Objective

Digital clubbing is regarded as the oldest clinical sign of medicine. The cause of this unique finger deformity has remained elusive throughout the centuries. For 3 decades our group has studied the etiology of this acropachy. This article reviews the current knowledge on the cause of digital clubbing.

Methods

PubMed database (www.pubmed.gov) was accessed. In clinical queries/clinical study service we entered “clubbing” or “hypertrophic osteoarthropathy,” choosing the “etiology” category with a “broad sensitive” search scope. The time span was from January 1975 to August 2006. Additionally, this article narrates the chronology of our research on the pathogenesis of clubbing.

Results

The many dreadful internal illnesses associated with digital clubbing have in common enhanced platelet/endothelial cell activation. Emerging evidence suggests that, in hypoxic conditions with extrapulmonary shunting of blood, large megakaryocyte fragments fail to enter the pulmonary circulation. Instead they gain access to the systemic circulation impacting at the most distal sites, there releasing growth factors and thus inducing clubbing. In cases of lung cancer, the purported growth factor could gain direct entrance to the systemic circulation. Vascular endothelial growth factor (VEGF) may play a central role in the development of digital clubbing. It is a platelet-derived factor induced by hypoxia, and it is also abnormally produced by diverse malignant tumors fostering their uncontrolled growth. On the other hand VEGF produces vascular hyperplasia, edema, and fibroblast/osteoblast proliferation. Such are clubbing histologic characteristics. Enhanced VEGF expression has been reported in practically all internal illnesses associated with this type of finger deformity. Recent studies have demonstrated high circulating levels as well as increased local expression of VEGF in different groups of patients with digital clubbing.

Conclusion

Abnormal expression of VEGF may be the cause of digital clubbing.

Section snippets

Data Source

PubMed database (www.pubmed.gov) was accessed. In clinical queries/clinical study service we entered “clubbing” or “hypertrophic osteoarthropathy,” choosing the “etiology” category with a “broad sensitive” search scope. The time span was from January 1975 to August 2006.

Data Extraction

All abstracts were reviewed. All studies that contained original data were selected, reviewed, and included in the discussion.

Results

Our PubMed search on the etiology of clubbing and HOA with the above-mentioned method yielded 165

Discussion

VEGF in the epicenter of clubbing/HOA could explain how different hypoxic or malignant diseases could induce the acropachy. As already stated, VEGF is a platelet-derived factor induced by hypoxia. Also, it is abnormally produced by diverse malignant tumors fostering their uncontrolled growth (20, 21). The multiple diseases associated with clubbing/HOA have in common the presence of prominent platelet and/or endothelial cell activation. In practically all of them enhanced VEGF expression has

Acknowledgments

I gratefully thank the many Rheumatology fellows in training that through the years took the initiative with enthusiasm and were key elements for the development of research protocols. Special recognition to my colleague Carlos Pineda, who was fundamental in the elaboration of the morphological studies.

References (46)

  • M. Martinez-Lavin

    Hypertrophic osteoarthropathy

  • E. Pineda et al.

    Hypertrophic osteoarthropathy in congenital cyanotic cardiopathy, description of 2 cases

    Arch Inst Cardiol Mex

    (1980)
  • M. Martínez-Lavín et al.

    Hypertrophic osteoarthropathy in cyanotic congenital heart disease: its prevalence and relationship to bypass of the lung

    Arthritis Rheum

    (1982)
  • G. Flavell

    Reversal of pulmonary hypertrophic osteoarthropathy by vagotomy

    Lancet

    (1956)
  • F. Greco et al.

    Loss of symptoms of pulmonary hypertrophic osteoarthropathy after laparotomy

    Ann Intern Med

    (1974)
  • M. Martínez-Lavín

    Digital clubbing and hypertrophic ostearthropathy: a unifying hypothesis

    J Rheumatol

    (1987)
  • D. Vazquez-Abad et al.

    Macrothrombocytes in the peripheral circulation of patients with cardiogenic hypertrophic osteoarthropathy

    Clin Exp Rheumatol

    (1991)
  • M. Matucci-Cerinic et al.

    von Willebrand factor antigen in hypertrophic osteoarthropathy

    J Rheumatol

    (1992)
  • C. Pineda et al.

    The skeletal manifestations of clubbing: a study in patients with cyanotic heart disease and hypertrophic osteoarthropathy

    Semin Arthritis Rheum

    (1985)
  • C. Pineda et al.

    Periostitis in hypertrophic osteoarthropathy

    AJR Am J Roentgenol

    (1987)
  • C. Fonseca et al.

    Circulating plasma levels of platelet-derived growth factor in patients with hypertrophic osteoarthropathy

    Clin Exp Rheumatol

    (1992)
  • M. Martínez-Lavín et al.

    Features of hypertrophic osteoarthropathy in patients with POEMS syndrome: a metaanalysis

    J Rheumatol

    (1997)
  • M. Soubrier et al.

    Growth factors in POEMS syndrome: evidence for a marked increase in circulating vascular endothelial growth factor

    Arthritis Rheum

    (1997)
  • Cited by (0)

    View full text