For our first episode, we discussed a topic that Avi covered in a tweetorial posted on February 29, 2020. Here’s a link to the full thread:
An ancient exam finding
Clubbing was first described 2,500 years ago by Hippocrates, making it perhaps the oldest physical finding in medicine. The term “clubbing” was coined in 1862 by Armand Trousseau (yes, that Trousseau) after observing patients with tuberculosis.
Though clubbing is classically associated with thoracic diseases like lung cancer, chronic obstructive pulmonary disease (COPD), and tuberculosis, it is not specific for any one entity. Instead, it typically indicates that something is going on systemically. It’s a hint that some digging is in order.
What is clubbing?
Clubbing is an increased curvature of the nail plate. While, for some, clubbing becomes a “you know it when you see it” finding, there are specific criteria, published in 1938 in the Lancet by Lovibond and Camb. While normal nails are concave at an angle of approximately 160 degrees, clubbed nails are convex at and angle greater than 180 degrees.
On exam, Schamroth’s sign (i.e., the loss of the window between opposed nails) is suggestive. In an ironic turn, Schamroth noticed his own clubbed nails after developing endocarditis.
But, why do fingers club?
In this episode, Avi discussed his original conception of the mechanism of clubbing: it had something to do with platelets and megakaryocytes not being filtered by the lung in patients with lung disease, then getting trapped in the fingers and causing clubbing.
But, because there are so many different diseases that cause clubbing, many of which don’t have anything to do with the lung, this suggested that there’s something else going on.
Surprisingly vascular endothelial growth factor (VEGF) kept coming up as an explanation. For one, all of the conditions that are associated with clubbing have high VEGF levels: tuberculosis, COPD, lung cancer, congenital heart disease, cirrhosis, and cystic fibrosis. Even inflammatory bowel disease. Supporting this association is finding that the histology of clubbing is characterized by abnormal vasculature with evidence of angiogenesis in the micro-vasculature.
Other forms of correlative evidence include:
- Active tuberculosis patients have much higher levels of VEGF than treated or latent tuberculosis patients (Figure)
- In those who have lung cancer, VEGF levels are significantly higher than in those with clubbing than in those who don’t have clubbing. In fact, resection of a lung adenocarcinoma expressing high levels of VEGF led to resolution of clubbing.
- High levels of VEGF are found in the mucosa of active inflammatory bowel disease, particularly Crohn’s disease.
- Increased VEGF levels are found in conditions associated with clubbing: COPD, congenital heart disease, and cirrhosis.
Any direct evidence implicating VEGF?
It turns out that cholinergic signaling (e.g., from the vagus nerve) can trigger VEGF release from endothelial cells. And, vagotomy (not something we typically do) which shuts down cholinergic signaling via the vagus nerve, helped relieve clubbing symptoms in a lung cancer patient.
After Avi posted the tweetorial, Hannah found additional evidence. One case report showed a decrease in the symptoms attributable to clubbing after treatment using the anti-VEGF antibody bevacizumab.
Returning to platelets, platelet micro-thrombi are indeed present in clubbed fingers. And, to connect everything together, VEGF is released by platelets!
Take home points
- Clubbing may be the oldest physical exam finding and associates with many systemic diseases.
- There is good evidence that increased VEGF levels connects these varied diseases as a unifying mechanism of clubbing. The increased VEGF leads to abnormal nail bed vasculature and the subsequent soft tissue changes of clubbing.
- Platelets secrete VEGF and plug nail capillaries, likely contributing to this pathogenesis.
Learning Objectives
- Identify the mechanisms that underlie fingernail clubbing.
- Understand why fingernail clubbing associated with so many different diseases?
- Recognize the potential diagnostic implications if a clinician notes clubbing on a patient’s hands.
CME/MOC
We are excited that The Curious Clinicians have partnered with VCU Health Continuing Education to offer continuing education credits for physicians and other healthcare professionals. Visit VCU Health for more information.
Listen to the episode
Credits & Citation
◾️Episode written by Avi Cooper
◾️Audio edited by Hannah Abrams
◾️Show notes by Tony Breu and Avi Cooper
Cooper AZ, Breu AC, Abrams HR. Why does fingernail clubbing happen in so many different diseases? The Curious Clinicians Podcast. June 3, 2020. https://curiousclinicians.com/2020/06/03/episode-1/
Opening image source: MedicineNet.com
The Curious Clinicians 