Hypertrophic osteoarthropathy: estrogens, prostaglandinE2, prostaglandin A2, and the inflammatory reflex.

It has been claimed that hyperestrogenism occurs in hypertrophic osteoarthropathy (HOA), but not in simple clubbing. However, one of our patients had simple clubbing and hyperestrogenism. We therefore measured estrogens, androgens, sex hormone-binding globulin (SHBG), and gonadotropins in five patients with HOA and in 18 patients with simple clubbing. Of the patients with HOA, 80% had a high urinary estriol concentration. In their serum, 80% had high estrone, 0% high estradiol, and 40% high SHBG. Of the patients with simple clubbing, 89% had a high urinary estriol concentration. In their serum, 76% had high estrone, 6% high estradiol, and 31% high SHBG. In all patients, urinary estriol concentration correlated positively with the degree of clubbing. Serum concentration of androstenedione, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was mostly normal, but androstenedione concentration correlated positively with the degree of clubbing. Spider angiomas were present in 74%, palmar erythema in 39%, and gynecomastia in 9%. Urinary creatinine concentration was low in 48% and correlated positively with the degree of clubbing. We reject the claim that hyperestrogenism occurs in HOA, but not in simple clubbing. Hyperestrogenism occurs both in HOA and in simple clubbing. Our results also support earlier reports that clubbing and HOA are associated with spider angiomas, palmar erythema, gynecomastia, adrenal cortical hyperfunction, muscle atrophy, and water retention. These results led to a new hypothesis on the pathogenesis of HOA, involving estrogens, prostaglandin E2, prostaglandin A2, and the inflammatory reflex.

Inaccurate pulse CO-oximetry of carboxyhemoglobin due to digital clubbing: case report.

Newer pulse CO-oximeters provide a non-invasive and quick means of measuring oxyhemoglobin, carboxyhemoglobin and methemoglobin. Clubbing has been reported to cause inaccuracy in pulse oximeters. We present a case of inaccurate carboxy-hemoglobin measurement by pulse CO-oximetry due to digital clubbing. An 18-year-old man with a history of cystic fibrosis presented after a suicide attempt by inhalation of exhaust. At the initial emergency department evaluation, his blood carboxyhemoglobin was 33%. He was intubated, placed on 100% oxygen and transferred to our facility. Upon arrival, we placed three different pulse CO-oximeters on different fingers and toes. Carboxyhemoglobin levels measured by these meters ranged from 9%-11%. A venous blood gas drawn on arrival showed a carboxyhemoglobin level of 2.3% after four hours on 100% oxygen by endotracheal tube. Thirty minutes later, we checked arterial blood gas, which revealed a COHb level of 0.9%. Again, non-invasive carboxyhemoglobin measurements read 10%. The patient was treated with hyperbaric oxygen for carbon monoxide poisoning. This case suggests that non-invasive measurements of carboxyhemoglobin should be correlated with the clinic history and with an arterial or venous blood gas oximetry analysis.

Interleukin (IL)-6 and receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) are increased in the serum of a patient with primary pachydermoperiostosis.

Primary pachydermoperiostosis (PDP) is a rare syndrome, characterized by digital clubbing, periostosis, and pachydermia. We have evaluated biochemical bone turnover markers, including components of interleukin-6 (IL-6) and osteoprotegerin/receptor activator of nuclear factor (NF)-kappaB ligand (OPG/RANKL) systems, in an 18-year-old man affected by primary PDP. The acute phase of the disease was characterized in our patient by high serum levels of IL-6 and RANKL. The observed high serum levels of these parameters are associated with increased values in markers of bone resorption (degradation products of C-terminal telopeptides of type-I collagen and urinary hydroxyproline/creatinine ratio) and reduced serum levels of bone alkaline phosphatase, a marker of bone formation. Serum levels of osteotrophic hormones were in the normal range. Our data suggest that, despite the radiographic findings, the acute phase of primary PDP is characterized by increased bone resorption, probably mediated by IL-6 and RANKL.

Vascular endothelial growth factor and hypertrophic osteoarthropathy.

OBJECTIVE: Hypertrophic osteoarthropathy (HOA) is characterized by the coexistence of digital clubbing and periosteal proliferation of the tubular bones. Localized vascular proliferation associated with platelet/endothelial cell activation are recognized features of this syndrome. Current knowledge suggests that HOA develops from the presence in the systemic circulation of one or more growth factors that are normally inactivated in the lungs. The nature of these purported growth factors has not yet been identified. Vascular endothelial growth factor (VEGF) has several features that may fit in with the pathogenesis of HOA. The objective of our study was to measure serum and plasma levels of VEGF in different groups of patients with HOA. METHODS: We studied 24 patients with HOA; of these, in 12 the HOA was secondary to cyanotic congenital heart disease and in 7 to lung cancer, while 5 represented primary cases. As controls we studied 28 individuals without HOA; of these, 12 were apparently healthy individuals, 7 had cyanosis secondary to chronic obstructive pulmonary disease, and 9 had lung cancer. ELISA was used to measure serum and plasma levels of VEGF. RESULTS: Plasma levels of VEGF were significantly higher in the patients with primary HOA (median 46.2; range 19.4-398.8 pg/ml) and in those with lung cancer-HOA (median 75.5; range 24.6-166.7), compared to healthy controls (median 7.4; range: 0-26.1), p < 0.05. Serum VEGF levels were higher in patients with lung cancer and HOA (median 411.4; range 164.2-959.5 pg/ml) compared with lung cancer patients without HOA (median 74.5; range 13.2-205.4), p < 0.001. CONCLUSIONS: Patients with primary HOA and those with HOA and lung cancer have increased circulating levels of VEGF. This cytokine may play a role in the pathogenesis of HOA.

Hypertrophic osteoarthropathy: endothelium and platelet function.

Hypertrophic osteoarthropathy (HOA) is characterized by finger clubbing, periostosis and arthritis. The pathogenesis of hypertrophic osteoarthropathy is still uncertain. Earlier studies have been focused on the potential role of platelet and endothelium in the pathogenesis of HOA. The aim of this study was to evaluate the circulating levels of endothelin-1 (ET-1), beta-thromboglobulin (beta-TG) and platelet-derived growth factor (PDGF) in 21 HOA patients. The circulating levels of ET-1, beta-TG were significantly higher in HOA patients vs healthy controls, but not vs controls with lung diseases. On the contrary, PDGF was significantly higher in HOA patients vs healthy controls and vs subjects with lung diseases. These findings suggest that "endothelium/platelet unit" may play a role in the pathogenesis of HOA, and PDGF could induce the changes observed in HOA.

The "endothelium/platelet unit" in hypertrophic osteoarthropathy.

Various pathogenetic theories of hypertrophic osteoarthropathy (HOA) have been proposed (neurogenic, hormonal, artero-venous shunts, genetic theory), but none of them is able to satisfactorily explain the genesis of HOA. The hypothesis of a central role of the "endothelium/platelet unit" was recently discussed. Above all, the release of the platelet derived growth-factor (PDGF) contained in platelet granules is particularly interesting. In order to assess the microvascular involvement in HOA we set up a research project whose aims were to evaluate the morphology of the capillary network at the nailfold, the dynamic aspects of microcirculation and in vivo platelet function. Since this study is still in progress, for the time being we present only a few preliminary results.

von Willebrand factor antigen in hypertrophic osteoarthropathy.

Recent evidence suggests that a key feature in the pathogenesis of hypertrophic osteoarthropathy (HOA) is an enhanced local platelet vessel wall interaction in the affected extremities. In our investigation we measured plasma levels of von Willebrand Factor Antigen (vWF:Ag; ELISA assay), a marker of platelet and/or endothelial activation, in 5 patients with the primary form of HOA and in 6 patients with the secondary form (due to cyanotic heart disease). Seven subjects matched for sex and age were used as controls. Patients showed statistically significantly higher levels of vWF:Ag in the primary (163.8 +/- 13.9%) and secondary form (152.6 +/- 9.6%, p less than 0.001 for both) when compared to controls (100.4 +/- 6.3%). Our results support the notion that platelet endothelial cell interaction may play a key role in the development of HOA.

Pachydermoperiostosis with gastric hypertrophy, anemia, and increased serum bone Gla-protein levels.

We evaluated a patient in whom pachydermoperiostosis occurred in conjunction with anemia and gastric hypertrophy. The mechanism of the anemia appears multifactorial because, besides a myelofibrosis, a serum inhibitor of the late stage of erythropoiesis was detected. The elevated serum bone Gla-protein (osteocalcin) favors the hypothesis that primary hypertrophic osteoarthropathy represents an imbalance between increased osteoblastic bone formation and normal bone resorption.

Growth hormone secreting carcinoma of lung and hypertrophic osteoarthropathy.

Plasma Human Growth Hormone (HGH) was raised in a patient with bronchial carcinoma and hypertrophic pulmonary osteoarthropathy before radiotherapy to the tumour. Though the soft-tissue swelling and pain of hypertrophic osteoarthropathy disappeared two to three weeks after radiotherapy to the carcinoma the HGH plasma levels were still very high at two months and came back to normal levels at six months and remained so at one year. It is suggested that ectopic production of HGH by the tumour in this case was not responsible for the changes of hypertrophic osterarthropathy.