Practice Essentials
Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by clubbing of the digits, periostitis of the long (tubular) bones, and arthritis. [1] It is also known as pachydermoperiostosis (PDP).
HOA can be primary (hereditary or idiopathic) or secondary. Secondary HOA, which accounts for about 80% of HOA cases, [2] is associated with an underlying pulmonary, cardiac, hepatic, or intestinal disease and often has a more rapid course. As a paraneoplastic syndrome, it most commonly occurs with pleural or pulmonary tumors; however, other tumors (eg, nasopharyngeal carcinoma and esophageal cancer) may also be involved. [3]
An evaluation for the primary condition is warranted in patients with possible secondary HOA; for example, a search for an intrathoracic malignancy or chronic infection. See Workup.
Therapy for HOA consists of treatment of the primary cause and symptomatic treatment. Examples of treatment of the primary cause include the following:
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Oncologic therapy for cancer (eg, surgical resection of tumor, chemotherapy, radiotherapy)
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Surgical correction of cardiac anomalies
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Antibiotics for infection
Symptomatic treatments include the following:
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NSAIDs
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Bisphosphonates
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Octreotide
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Vagotomy
See Treatment.
Background
The clinical triad of digital clubbing, arthralgias, and ossifying periostitis that characterizes hypertrophic osteoarthropathy (HOA) has been recognized since the late 1800s and was previously known as hypertrophic pulmonary osteoarthropathy (HPOA). Hippocrates first described digital clubbing 2500 years ago, hence the use of the term Hippocratic fingers. [4] Observations made in modern times by Eugen von Bamberger (1889) [5] and Pierre Marie (1890) [6] led to the term Marie–Bamberger disease. [7] Work by other investigators led to identification of various causes of this digital anomaly, which can be the first manifestation of a severe organic disease such as chronic pulmonary and cardiac diseases, [8]
HOA is classified either as primary (hereditary or idiopathic) or secondary. Primary hypertrophic osteoarthropathy (PHO; also termed primary pachydermoperiostosis or Touraine-Solente-Gole syndrome) was initially described by Friedreich in 1868 and then by Touraine et al in 1935, who recognized its familiar features and proposed the following classification [9, 10] :
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Complete - Pachydermia, digital clubbing, and periostosis
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Incomplete - No pachydermia
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Forme fruste - Prominent pachydermia with few skeletal manifestations
In some cases, the diagnosis of HOA as primary can be challenged with the development of a disease that is known to be associated with secondary HOA. This may occur as late as 6-20 years after the appearance of HOA. [11, 12]
Clubbed digits
Clubbing is characterized by elevation of the nail and widening of the distal phalanx caused by swelling of the subungual capillary bed resulting from increased collagen deposition, interstitial inflammation with edema, and proliferation of the capillaries themselves. [13] Perivascular infiltrates of lymphocytes and vascular hyperplasia are responsible for thickening of the vessel walls. Electron microscopy reveals Weibel-Palade bodies and prominent Golgi complexes, confirming structural vessel wall damage. [14] Vast numbers of arteriovenous anastomoses may also be seen in the nail bed. [15]
Two types of bone changes can be found in the distal phalanges, hypertrophic and osteolytic. [16] Hypertrophy or bony overgrowth predominates in patients with HOA secondary to lung cancer, whereas acro-osteolysis predominates in patients with HOA secondary to cyanotic congenital heart disease. [17] The type of bone remodeling process depends on the age when clubbing develops. [16] If clubbing appears in childhood, osteolysis is more prominent; however, if it develops after puberty, hypertrophic changes take place. Pineda et al hypothesize that a putative circulating growth factor destroys immature bone. [16]
Periosteum
The pathologic hallmark of HOA is neoangiogenesis, edema, and osteoblast proliferation in distal tubular bones that lead to subperiosteal new-bone formation. Subperiosteal new bone formation exists along the distal diaphysis of tubular bones, progressing proximally over time. The irregular periosteal proliferation affects predominantly the distal ends of long bones, including the epiphysis in 80-97% of patients. Usually the metacarpals, metatarsals, tibia, fibula, radius, ulna, femur, humerus, and clavicle are involved. The tibia is almost invariably involved. [18, 19, 20] Involvement of the epiphysis distinguishes it from the secondary form, which typically spares the epiphysis.
Initially, excessive connective tissue and subperiosteal edema elevate the periosteum; then, new osteoid matrix is deposited beneath the periosteum. [18] As this mineralizes, a new layer of bone is formed, and, eventually, the distal long bones may become sheathed with a cuff of new bone. [21]
Synovium
Synovial involvement may occur with subperiosteal changes. [18] Thickening of the subsynovial blood vessels and mild lining-layer hyperplasia may occur. [22, 18] The edematous synovium becomes mildly infiltrated with lymphocytes, plasma cells, and occasional polymorphonuclear leukocytes, but the results of immunohistologic studies are negative. Electron-dense subendothelial deposits are present in vessel walls. [23, 24, 25] In a study of a patient with primary HOA and chronic arthritis, Lauter et al found multilayered basement laminae around small subsynovial blood vessels consistent with the late stages of vascular injury. [25] Synovial fluid is usually noninflammatory with low leukocyte counts and few neutrophils. [23, 25]
Skin
Skin changes are more evident in primary HOA and are caused by dysregulation of mesenchymal cells. [26] Characteristic cutaneous manifestations include pachydermia (ie, thickening of facial skin resulting in leonine faces) over the scalp, cutis verticis gyrata, and bilateral ptosis over the eyes resulting in blepharoptosis. [27] These changes yield a characteristic “bulldog” appearance. [28]
Other dermatologic manifestations are acne, eczema, seborrhea, and palmoplantar hyperhidrosis. The skin of the hands and feet are also thickened, but usually not folded.
Pathophysiology
The development of hypertrophic osteoarthropathy (HOA) has been linked to several mechanisms, including excessive collagen deposition, endothelial hyperplasia, edema, and new bone formation. [29] It has been hypothesized that these mechanisims are driven by paraneoplastic growth factors, [30] such as prostaglandin E and other cytokines; and neurologic, hormonal, [31] and immune mechanisms. [32, 18] All, or at least many, likely contribute to its development in different clinical situations. A popular current theory involves the interaction between activated platelets and the endothelium, which is discussed further below. [30, 32, 33] Primary and secondary HOA have distinct pathophysiologies despite similar clinical presentations.
Primary HOA has been linked to mutations in two genes, 15-hydroxyprostaglandin dehydrogenase (HPDG) [34] , and solute carrier organic anion transporter family, member 2A1 (SLCO2A1). [35] Both autosomal dominant inheritance with incomplete penetrance and recessive inheritance have been reported. [2] The mutations of HPDG and SLCO2A1 lead to elevation of prostaglandin E2 (PGE2) with decrease in the level of its metabolites. Under normal conditions, PGE2 is degraded into unstable 13, 14-dihydro-15-keto PGE2 and then into stable 13, 14-dihydro-15-keto PGA2, with 15-PGDH as a key enzyme in the catabolic pathway. [36] Increased PGE2 levels have been shown to stimulate activity of both osteoclast and osteoblast, which may contribute to the skeletal manifestations of primary HOA, including periostosis and acro-osteolysis. [37, 38]
Kozak et al tested the hypothesis that elevated systemic levels of PGE2 in patients with lung cancer contributes to digital clubbing. This study found that the median urinary level of the metabolite of prostaglandin E2 was 2.3-fold higher in patients with clubbing than in patients without clubbing. [39]
Secondary HOA, on the other hand, is most often associated with an underlying pulmonary disease, mainly bronchogenic carcinoma. HOA has been observed in up to 17% of bronchogenic carcinoma patients. [40] Secondary HOA can also be associated with non-pulmonary conditions, including cardiovascular, gastrointestinal, hepatobilliary, and endocrine diseases [40]
Several other pathophysiologic mechanisms have also been observed in HOA. The most important of these mechanisms involve circulating signaling molecules and growth factors that are normally cleared from the blood by the pulmonary endothelium. [22]
Normally, megakaryoctes released from bone marrow into the general circulation travel to the pulmonary microvasculature, where they fragment into platelets. [41] If that fails to occur, the platelet precursors can become trapped in the peripheral vasculature, where they release platelet-derived growth factor and vascular endothelial growth factor, which promote vascularity. [42] This has been demonstrated in patients with cyanotic heart diseases, in which large circulating platelets with abnormal, and at times bizarre, morphology have been found. Those macrothrombocytes are responsible for the aberrant platelet volume distribution curves. [43, 32]
To date, several physiologic and anatomic processes have been defined in which these large particles reach the fingertip capillaries and impact release of growth factors. Megakaryocytes or megakaryocyte fragments have been observed bypassing the lung capillary network (eg, in patients with right-to-left intracardiac shunts, carcinoma of the bronchus, anatomic malformation of the vasculature, patent ductus arteriosus complicated by pulmonary hypertension and a right-to-left shunt) and forming large platelet clumps on the left side of the heart or in large arteries (eg, subacute bacterial endocarditis, subclavian aneurysm), or chronic platelet excess (eg, in chronic inflammatory bowel disease). [44]
For the reasons above, cyanotic heart diseases are an excellent model for studying HOA pathogenesis because more than one third of patients with lifelong clubbing secondary to cyanotic heart disease eventually display the full HOA syndrome. [45] HOA caused by intrapulmonary shunting of blood becomes evident only in the limbs that receive unsaturated blood, for example, in patients with patent ductus arteriosus complicated by pulmonary hypertension and a right-to-left shunt.
The growth factors released by megakaryocytes or megakaryocyte fragments impacted at distal sites include bradykinin, slow-reacting substance of anaphylaxis, transforming growth factor–β1 (TGF-β1), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) stored in the platelet alpha granules. Those are all angiogenic, with trophic effects on capillary beds. In addition, they all enhance the activity of osteoblasts and fibroblasts. This initiates finger clubbing by inducing connective-tissue matrix synthesis periostosis. [32, 33]
Increased circulating growth factor levels thus would explain all of the features of HOA. PDGF and VEGF are thought to contribute significantly to the development of HOA. VEGF is a platelet-derived factor whose action is induced by hypoxia. It is a potent angiogenic and permeability-enhancing factor, as well as a bone-forming agent. VEGF receptors are expressed in subperiosteal bone-forming cells. Both PDGF and VEGF induce vascular hyperplasia, new bone formation, and edema. [46]
In keeping with this hypothesis, Matucci-Cerinic et al have shown elevated von Willebrand factor antigen (vWF:Ag) levels in persons with primary HOA and in persons with HOA secondary to cyanotic heart disease. [32] vWF:Ag is a surrogate marker of endothelial activation and damage, as shown by the fact that high plasma levels of vWF:Ag are also found in the vasculitides, myocardial infarction, diabetic microangiopathy, and scleroderma. [32] Thus, a common pathogenetic pathway for HOA possibly involves localized activation of endothelial cells by an abnormal platelet population. Macrothrombocyte and endothelial cell activation can also be present in cases of HOA associated with other disease entities such as liver cirrhosis, in which a prominent intrapulmonary shunting of blood occurs. [33]
Stimulation of fibroblasts by PDGF, epidermal growth factor (EGF) and TGF-β along with overexpression of VEGF have also been linked to the extensive myelofibrosis seen in a few cases of pachydermoperiostosis. [47]
A second proposed mechanism for the development of hypertrophic pulmonary osteoarthropathy is a vagally-mediated alteration in limb perfusion. Interestingly, the anatomic distribution of vagal nerve fibers correlates to the area of clubbing. Vagotomy and sympatholytic drugs have been reported to reverse or to improve HOA, suggesting a role for reflex vagal stimulation. [48] Bazaar et al proposed that sympathetic override of the normal protective function of vagal innervation is the basis of HOA. [49] Sympathetic activity has been noted to induce cytokine changes consistent with inflammation.
Among these, epinephrine has been shown to induce production of interleukin (IL)-11 in human osteoblasts. Recombinant IL-11 has been shown to cause reversible symmetric periostitis in the extremities. In diseased states, autonomic stimulation may occur as a result of chemoreceptor activation in response to acidosis, hypoxia, or hypercapnia. Examples include sleep apnea, congestive heart failure, renal failure, and tumor-induced hypoxia. Reversal of those conditions with removal of the associated lung neoplasm or correction of a cyanotic heart malformation suggests that alteration of lung function plays an important role. [30]
A third mechanism is the possibility of ectopic production of hormonelike substances (such as VEGF) by tumor or inflammatory tissue, resulting in excessive circulating levels of angiogenic substances that would cause capillary bed hypertrophy and periosteal reaction, as noted earlier. Elevated circulating concentrations of VEGF and evidence of tumor production of VEGF have been found in lung cancer. [50] Following tumor resection, the concentrations of VEGF markedly decline, which also correlates with clinical improvement. Increased levels of VEGF and IL-6 caused by the genetic mutation of K-ras might play a role in the pathogenesis of HOA with lung cancer. [51]
Diverse types of cancers produce VEGF as a mechanism of tumor dissemination. Abnormal expression of VEGF is also known to occur in non-neoplastic diseases associated with HOA, such as Graves disease and inflammatory bowel disease. These diseases are characterized by prominent endothelial cell involvement, leading to overproduction of VEGF and thus acropachy. In HOA related to vascular prosthesis infection, Alonso-Bartolome et al suggested involvement of the humoral pathway giving rise to graft infection–associated HOA syndrome by endotoxin or vasoactive compound activated or released by bacteria adherent to the graft. [8]
Chronic activation of macrophages secondary to pulmonary pathologies may lead to digital clubbing by continual production of profibrotic tissue repair factors (eg, growth factors, fibrogenic cytokines, angiogenic factors, remodelling collagenases). These factors act systemically, but their effect is greatest at those parts of the vasculature which are most sensitive to these actions, such as the nail beds. Hypoxia also triggers the activation of macrophages. [52]
The role of different cytokines and cell receptors, including IL-6 and the osteoprotegerin or RANKL (receptor activator of nuclear factor kappa-Β ligand) system have been described on the development of the disease. Higher serum levels of IL-6 and RANKL 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, suggesting that HOA is characterized by increased bone resorption, probably mediated by IL-6 and RANKL. [53, 54]
Studies in patients with PDP or PHO evidenced increased plasma levels of several substances, such as endothelin-1, β-thromboglobulin, platelet-derived factor, von Willebrand factor, and vascular endothelial factor, among others, which could have a role in disease progression and periosteal proliferation. [54]
The pathogenesis underlying the higher risk of HOA in males, as proposed by Bianchi et al, relates to the high levels of nuclear steroid receptors, increased cytosolic estrogen receptors, and absence of detectable progesterone and androgen cytosolic receptors in HOA. Those suggest increased tissue sensitivity to different circulating sex steroids, which could enhance tissue epidermal growth factor or transforming growth factor alpha production and use. [53]
HOA can be associated with pregnancy and aging secondary to platelet abnormalities, hormonal disturbances, and cytokine dysfunction.
Enhanced Wnt genetic signaling contributes to the development of pachydermia skin changes in primary HOA by enhancing dermal fibroblast functions. [26]
Epidemiology
Frequency
Primary hypertrophic osteoarthropathy (HOA) is a rare condition. The precise incidence of this syndrome is unknown. According to one study, it has an estimated prevalence of 0.16%. [55]
No systematic prevalence studies have been performed for secondary HOA, but cases are associated with many illnesses. According to Rassam et al, HOA occurred in about 3% (9 of 280) of consecutive lung cancer cases seen between 1970-1975. Other literature has described higher rates in primary lung cancer, ranging from about 4% to 32%. [8]
In a study of consecutive patients with congenital cardiac disease, Martínez-Lavín et al identified HOA in 10 of 32 patients (31%). [56] HOA associated with respiratory failure is reported to be present in 2–7% of patients.
Mortality/morbidity
Primary HOA has a self-limiting course, with progression stopping at the end of adolescence. There is no cure for the skeletal abnormalities. [12] The mortality and morbidity of secondary HOA vary with the associated illness. Secondary osteoarthritis may complicate long-standing HOA.
Race-, sex-, and age-related demographics
HOA affects persons of all races. Primary HOA has a marked predominance in males, with a male-to-female ratio of 9:1. [57] It has an autosomal dominant pattern of inheritance, with mainly variable expression and incomplete penetrance and familial aggregation in 25-38% of cases. [10, 28] Recessive autosomal inheritance and X-linked mutations may also occur, but those cases may differ in severity and prevalence of clinical features. [2] Secondary osteoarthropathy has the same sex ratio as the associated illnesses.
Primary HOA has a bimodal peak of onset: the first is before age 1 year and the second is at around the age of puberty (ie, approximately 15 years). [57] Secondary HOA is rarely encountered in children and adolescents; it most commonly affects individuals aged 55-75 years. [8]
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Clubbing associated with hypertrophic osteoarthropathy can be classified into 3 topographical groups (ie, symmetrical, unilateral, unidigital). This is symmetrical clubbing; it involves all the fingers.
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Joint symptoms of hypertrophic osteoarthropathy range from mild to severe arthralgias that involve the metacarpal joints, wrists, elbows, knees, and ankles. The range of motion of affected joints may be slightly decreased. When effusions are present, they usually involve the large joints (eg, knees, ankles, wrists).
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For hypertrophic osteoarthropathy diagnosis, radionuclide bone scan using technetium Tc 99m polyphosphate shows increased uptake of the tracer in the periosteum, often appearing pericortical and linear in nature. These findings can be present even when findings from plain radiographs are doubtful. The clubbed digits may also show increased uptake in early passage flow studies.
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In adulthood, 90% of generalized hypertropic osteoarthropathy cases are associated with an intrathoracic infectious or neoplastic condition.
