Digital clubbing: forms, associations and pathophysiology.

Among proposed mechanisms to explain digital clubbing, the release of cytokines, specifically vascular endothelial growth factor and platelet-derived growth factor, from aggregated platelets and megakaryocytes has emerged as the most likely explanation. This review describes these and other contributory processes.

Cyclooxygenase-2 Expression in Non-Small Cell Lung Cancer Correlates With Hypertrophic Osteoarthropathy.

Hypertrophic osteoarthrpathy (HO) is a rare paraneoplasic syndrome associated with non-small cell lung cancer (NSCLC). The pathophysiology of HO is unknown but was recently related to enhanced levels of urine prostaglandin E2 (PGE2). Here, we report the case of a patient that presented HO in association with a resectable left upper lobe NSCLC. Following surgery and adjuvant chemotherapy, HO resolved and did not recur with development of a brain metastasis 1 year later. Interestingly, tumor cyclooxygenase-2, an enzyme responsible the synthesis of PGE2, was expressed in the primary tumor but not in the resected metastasis.

Primary hypertrophic osteoarthropathy: an update.

Digital clubbing, which has been recognized as a sign of systemic disease, is one of the most ancient diseases. However, the pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood. The study of a clinically indistinguishable idiopathic form (primary hypertrophic osteoarthropathy, PHO) provides an opportunity to understand the pathogenesis of hypertrophic osteoarthropathy. Current advances in the study of PHO are discussed. The impaired metabolism of prostaglandin E2 (PGE2) plays a central role in its pathogenesis.

Exploring the cause of the most ancient clinical sign of medicine: finger clubbing.

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.

Hypertrophic osteoarthropathy pathogenesis: a case highlighting the potential role for cyclo-oxygenase-2-derived prostaglandin E2.

BACKGROUND: A 65-year-old woman presented with weakness, 9 kg weight loss, dysphagia, facial and bilateral upper-extremity swelling, and debilitating, bilateral lower-extremity pain. The patient had undergone a right upper lobectomy for a 5 mm, poorly differentiated adenocarcinoma of the lung 4 years previously. Medical history included chronic obstructive pulmonary disease (emphysema), hypertension, cerebrovascular disease and multinodular goiter. Surgical history included a right carotid endarterectomy. The patient's history was remarkable for 50+ pack-years of smoking. INVESTIGATIONS: Physical examination, comprehensive metabolic panel and complete blood counts, CT, bone scintigraphy, quantification of urinary 11a-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (also known as PGE-M). DIAGNOSIS: Recurrent non-small-cell lung cancer with adrenal metastasis, hypertrophic osteoarthropathy associated with non-small-cell lung cancer, and hyperprostaglandinuria. MANAGEMENT: Rofecoxib 25 mg daily for hypertrophic osteoarthropathy, palliative external-beam radiation (44 Gy in 22 fractions) for mediastinal mass, palliative external-beam radiation (30 Gy in 12 fractions), followed 2 years later with radiofrequency ablation, for left adrenal metastasis.

Circulating vascular endothelial growth factor concentrations in a case of pulmonary hypertrophic osteoarthropathy. Correlation with disease activity.

Vascular endothelial growth factor (VEGF) is a cytokine overexpressed in hypoxic and malignant pathologies. VEGF induces vascular hyperplasia, new bone formation, and edema. These histological abnormalities characterize hypertrophic osteoarthropathy. We describe a case of pulmonary hypertrophic osteoarthropathy with high circulating VEGF levels. Removal of the lung tumor led to a dramatic disappearance of the skeletal abnormalities and to reduction of circulating VEGF levels. Histochemical studies of the excised tumor confirmed abnormal VEGF production.

[The biochemical markers of bone metabolism in differential diagnosis of hematogenic osteomyelitis of foot bones and acute stage of diabetic osteoarthropathy]. / Biokhimicheskie markery kostnogo metabolizma v differentsial'noi diagnostike gematogennogo osteomielita kostei stopy i ostroi stadii diabeticheskoi osteoartropatii.

The determination of the level of leukocytes and ESR in 25 patients was shown to be of low informative value in differential diagnostics of destructive injuries of feet in patients with diabetes mellitus. An analysis of the biochemical markers of the bone remodeling has demonstrated high informative value of this method in differential diagnostics of acute stage of diabetic osteoarthropathy and osteomyelitis that allows to use it in complex examinations of osteomyelitis suspects.

[Review on hypertrophic osteoarthropathy and digital clubbing]. / Le point sur l'ostéoarthropathie hypertrophique et l'hippocratisme digital.

Clubbing was first described by Hippocrates more than 2.500 years ago. It may be seen alone or as part of an entity called hypertrophic osteoarthropathy which include periostitis, arthritis and sometimes thickening and edema of the skin around the affected joints. Pulmonary diseases such as cancer, abscess, empyema, bronchiectasis and cystic fibrosis are the major diseases known to be associate with hypertrophic osteoarthropathy. Digestive tract cancer, cyanogenic congenital heart disease are well known association. Many theories have attempted to explain the appearance of this sign but few have persisted. In this article, we review characteristics, relation with etiology and the basis of the pathophysiology of hypertrophic osteoarthropathy and particularly of clubbing.

Hypertrophic pulmonary osteoarthropathy associated with non-small cell lung cancer demonstrated growth hormone-releasing hormone by immunohistochemical analysis.

Hypertrophic pulmonary osteoarthropathy (HPO) associated with non-small cell lung cancer in a 58-year-old man was accompanied by an elevated serum level of growth hormone (GH). HPO rapidly disappeared after resection of the primary tumor and the elevation of serum GH was resolved. Immunohistochemically the tumor contained growth hormone-releasing hormone (GHRH) but not GH. These findings suggest that the high serum GH level due to ectopic GHRH production in the tumor, was a contributing factor in HPO. This is the second reported case of non-small cell lung cancer which was immunohistochemically positive for GHRH associated with HPO.

Beta-2-microglobulin-associated amyloidosis.

beta2-Microglobulin-associated amyloidosis has emerged as a major complication of long-term renal replacement therapy. The syndrome is confined to those patients on nontransplant modes of therapy. It does not occur in patients with a functioning renal transplant or, if already present, it does not progress any further in such patients. In the population of ESRD patients on dialysis, beta2-microglobulin-associated amyloidosis affects most patients treated for more than 15 years and is a cause of significant morbidity and in rare cases even mortality. The present review, which is based on the presentation of a typical case, discusses the current knowledge on the pathogenesis, clinical manifestations, diagnosis, prevention and therapy of beta2-microglobulin-associated amyloidosis.

Digital clubbing. Demonstration with positron emission tomography.

Digital clubbing is a classic cutaneous manifestation of pulmonary disease, but its mechanism is unknown. We describe a patient with lung cancer and clubbing in whom positron emission tomography (PET) demonstrated, for the first time, that increased glucose metabolism occurs at the nailbed. PET may contribute to future investigations of digital clubbing.

Hypertrophic osteoarthropathy and thyroid cancer.

We describe a case of aggressive undifferentiated thyroid cancer associated with rapidly evolving hypertrophic osteoarthropathy (HOA) that developed at the time of pulmonary dissemination of the thyroid neoplasm. The syndrome appeared to be paraneoplastic, possibly due to a substance normally cleared by the lungs.

Clubbing associated with oesophageal adenocarcinoma.

A patient with an oesophageal adenocarcinoma, recent onset of digital clubbing, and evidence of increased oestrogen synthesis is presented. In the discussion, some of the theories of the pathogenesis of clubbing are reviewed, together with previous reports of clubbing in gastro-oesophageal disorders. A possible unifying theory is proposed for our case which we believe is the first report of this triple association.

[Hypertrophic osteopathy in alcoholic males]. / Alkoholbeteg férfiak hypertrophiás osteopathiája.

Hypertrophic osteopathy was observed in 5 alcohol addict men. Periosteal newbone formation on the femur, tibia, fibula, radius and ulna appeared symmetrical. The short tubular and flat bones of hands and feet did not suffer impairment. Liver biopsy confirmed in each case portal cirrhosis. Hypertrophic osteopathy is a late complication of alcohol disease. Its development may be due to individual predisposition influenced by nutritional, hormonal, genetic, pancreatohepatic and biomechanical factors.

Clinical studies of bone metabolism using a simple model of calcium tracer kinetics.

Bone metabolism studies were performed in 44 subjects with and without bone disease using a calcium tracers kinetics model, the central feature of which is an expanding exchangeable calcium pool. In normal subjects the accretion rate and the exchangeable calcium pool ranged from 1.49 to 8.45 (mean 3.9 +/- 2.05) mg.d-1kg-1 and from 60 to 131 (mean 81.25 +/- 18.11) mg.kg-1, respectively. The patients with osteogenesis imperfecta. Pierre Marie's disease and one out of two cases of hypoparathyroidism had values which fell within the normal range. Both the accretion rate and the exchangeable calcium pool were significantly elevated in patients with Paget's disease and with hyperparathyroidism. Uremic patients with generalized bone lesions had accretion rates or both parameters elevated. As far as patients with successful renal transplant are concerned, the results suggest that this method is a very poor means for detecting bone disorders with only focal lesions. In contrast, the method can be very useful when persistent renal osteodystrophy or secondary hyperparathyroidism are suspected.