Hypertrophic Osteoarthropathy (HOA)

Hypertrophic osteoarthropathy (HOA) is a syndrome defined by the presence of a bulbous deformity of the tip of the fingers conventionally known as digital clubbing. This deformity is associated to thickening of the outer layer of the long bones. Proliferation and activation of the small blood vessels at the distal parts of the extremities is another outstanding feature of this syndrome. It is very important to recognize HOA because in the majority of cases the presence of this disorder indicates the existence of another serious illness such as lung cancer, congenital heart defects or liver cirrhosis (among many others). Nevertheless it should be mentioned that in a very small group of patients, HOA is present without any underlying illness, developing what is known as primary HOA.

What causes hypertrophic osteoarthropathy ?

Any theory explaining the causes of HOA should answer the following questions :

· Why and how different diseases can induce the same syndrome ?

· What is the explanation to the unique tissue overgrowth, and the proliferation and activation of the small blood vessels located at the most distal parts of the extremities ?
 

In 1987 I proposed a unifying hypothesis that has been subsequently confirmed by experimental data:

Recognizing that most of the diseases associated to HOA alter some of the lung functions, It was proposed that such alterations could be due to a fraction of the blood flow bypassing the lung (clearly evident in cases of congenital heart malformations and in a lesser degree in lung cancer and in liver cirrhosis). It was suggested that HOA develops by the presence in the systemic circulation of a growth factor normally inactivated in the lungs. Subsequently, Dickinson and Martin have suggested that such growth factor could be platelet-derived. They based their proposal on a mathematical model that suggests that in normal circumstances all platelets are generated in the lung as result of the progressive megakaryocyte fragmentation in the highly subdivided pulmonary tree. In cases of lung bypass, megakaryocytes would directly enter the systemic circulation and interact with blood vessel cells at the most distal parts of the extremities releasing growth factor(s) and thus inducing finger clubbing.

Our studies with patients with congenital heart malformations agree with this theory. Such patients have a platelet population with peculiarities that fit the above mentioned model. We have also found that patients with HOA have signs of platelet/endothelial cell activation as manifested by the increased circulating levels of von Willebrand factor antigen. Additionally, patients with HOA associated to lung cancer and patients with primary HOA have high circulating vascular endothelial growth factor levels. This growth factor is produce by diverse malignant tumors as mechanism of growth. It is also produced by platelets. Low oxygen concentrations promote its actions. All these features favor a central role of vascular endothelial growth factor in the development of HOA.

 

Clinical investigations :
 

· Contrary to the general held notion that suggested that HOA was extremely rare in patients with cyanotic congenital heart defects, our prospective study demonstrated that one third of such patients have evidence of HOA

· The “digital index” has been proposed as a bedside method to define the severity of finger clubbing.

· The proliferation of the outer layer of the bones can be appreciated in areas of the extremities not covered by muscles such as the wrists and ankles.

· An analysis of described patients with a peculiar illness known as POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M component and Skin Changes) found that the majority of them have the most conspicuous features of HOA. It appears that there is a significant overlap between HOA and POEMS syndrome.

· The primary form of HOA has peculiar characteristics : a clear hereditary predisposition with the overwhelming majority of affected persons being male. Patients with primary HOA display a more generalized skin overgrowth associated with acne and increased perspiration.
 

Radiological investigations :

· Digital clubbing is characterized by remodeling of the underlying bone.

· The proliferation of the outer parts of the bone follows an orderly process : in early stages it affects few bones (usually tibias and fibulas) involving only their middle section. In advanced stages practically all bones are affected and individual bones are affected in its entirety.

· The peculiar distribution of bone involvement allows the differentiation of HOA from other bone pathologies and also allows its recognition centuries after the death of the individuals by carefully studying their skeletal remains (we have found evidence of this disorder in ancient human skeletal remains from pre-Hispanic Mexico).
 

The study of HOA has been fascinating. The definition of its mechanisms would undoubtedly help to better understand the peculiarities of the lung micro-circulation, as well as the function of growth factors and the biology of cancer.
 

Bibliography :

Please see references in my resume.

 

Manuel Martínez-Lavín MD.
Internist and Rheumatologist

doctor@martinez-lavin.com