Excerpt from Dupuytren Contracture

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Background

Dupuytren contracture is a palmar fibromatosis of uncertain etiology. Reports were first seen in 17th century European medical literature, well before the eponymous Baron Dupuytren, a prominent French surgeon, performed his first palmar fasciotomy in 1831. Dupuytren presented his findings at a lecture, the exact words of which were subsequently disseminated widely by his students, leading to the adoption of his name for the condition.

The syndrome is characterized by fibrosis of the palmar fascia leading to flexural contraction of the digits, which is often progressive. Both the proximal interphalangeal (PIP) joint and the metacarpophalangeal (MCP) joint may be affected. Although many cases appear to be idiopathic and without coexistent conditions, a variety of associated diseases have been reported.

Therapies include conservative medical and surgical modalities. Although the condition is not fatal, significant morbidity can occur if patients remain untreated.

For additional information, see the following articles from eMedicine and Medscape:

• Dupuytren Contracture (orthopedic surgery focus)
• Dupuytren Contracture (rheumatology focus)
• Dupuytren Contracture (physical medicine and rehabilitation focus)
• New Approach for Dupuytren's Contracture: A Newsmaker Interview With Charles Eaton, MD
• Viewpoint: When Is Surgery Warranted in Dupuytren's Contracture?

Pathophysiology

The etiology and the mechanisms of formation have not been fully determined. The disease affects the palmar fascia, not the tendons, although the cordlike fascial thickening can be mistaken for a thickened tendon.

In the fascia, 3 stages have been described, as follows:

• Proliferative phase: Local fascial fibroplasia and development of a nodule, in which myofibroblasts proliferate, occur.
• Involutional phase: Myofibroblasts align themselves along the tension lines within the nodule.
• Residual phase: The nodular tissue disappears, leaving acellular tissue and thick bands of collagen. The ratio of type III collagen to type I collagen increases, which is the reverse of the normal pattern in the palmar fascia.

These cellular changes are similar to those that occur in localized microvascular ischemia and scar formation, leading some authors to believe that these factors may be the causes of the initial fibroblast and myofibroblast proliferation. Microvascular ischemia occurs as a result of the conversion of adenosine triphosphate to hypoxanthine, which is then oxidized by xanthine oxidase. This conversion releases free radicals, which induce fibroblast proliferation and the production of interleukin (IL)–1.

Various mediators released by platelets and macrophages have been implicated in the pathogenesis of Dupuytren contracture. These mediators include IL-1 and transforming growth factors (TGFs)–beta1 and –beta2. TGF-beta1 and –beta2 have 4 main effects, as follows:

• Differentiation of fibroblasts to myofibroblasts
• Increased production of components of the extracellular matrix, including collagen type III
• Splicing of fibronectin
• Activation of platelets to produce lysophosphatidic acid (LPA)

The linkage of alpha5-beta1 integrin to extracellular fibronectin, as well as the interaction of TGF-alpha and epidermal growth factor-receptor during the proliferative and involutional phases,¹ appear to have a role in enhancing tissue contractility in palmar fibromatosis. LPA and prostaglandin factor 2 are agonists that induce myofibroblast contraction. Levels of nerve growth factor, which induces fibroblast transformation to myofibroblasts, were also found to be increased in persons with Dupuytren tissue, especially during stages II-III.

Inflammation and skin tension may also cause fibromatosis. Histologically, the lesion shows characteristic bundles of fibroblasts separated by collagen fibers. Multinucleated giant cells may also be present. Lymphocytes, macrophages, and increased numbers of S100-positive Langerhans cells and CD45⁺ cells have been found in nodules and at dermoepidermal junctions. One report suggested a role of factor XIIIa⁺ cells in the affected tissue.

The interaction of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMP), and A disintegration and metalloproteinase domain with thrombospondin motif (ADAMTS) is also responsible for Dupuytren changes. In particular, levels of MMP-1, MMP-3, MMP-7, MMP-14, TIMP-1, and ADAMTS-14 are all increased in affected tissues, resulting in increased collagen biosynthesis, decreased collagenolysis, and contraction.²

Continuing research into the pathogenesis of Dupuytren contracture has yielded information that may be valuable in understanding and developing new therapies for this disease, as follows:

• TGF-beta1 at 1-10 ng/mL induces myofibroblast proliferation, leading to contraction. However, according to one report, at 20-30 ng/mL, negative feedback inhibition of TGF-beta1 occurs, resulting in decreased myofibroblast activity.
• N-acetyl-L-cysteine (NAC), a substance that has antifibrotic properties in hepatic stellate cells and rat fibroblasts, has also been shown to down-regulate the Smad signaling pathway (downstream of TGF-beta1), leading to decreased expression of fibrogenesis-related proteins.³

Frequency

United States

No prospective studies have been performed to determine the incidence of Dupuytren contracture, but a cross-sectional study looking at the prevalence in 5000 patients admitted to a New York City hospital for unrelated conditions showed a rate of 4.8%, with a male-to-female ratio of 3:1.

International

Studies have been performed worldwide, yet a range of frequencies has been reported. The highest frequency was reported in Scotland, where 200 patients were examined and 39% of men and 21% of women older than 60 years were affected with Dupuytren contracture. In Japan, 19.7% of men and 9% of women older than 60 years in nursing homes had the disease. In Spain, the disease was seen in 9.9% of individuals aged 45-54 years, while the rate increased to 25.5% in patients older than 75 years. In Iceland, rates of 7.2% in men aged 45-49 years and 39.5% in men aged 70-74 years have been reported.

Mortality/Morbidity

No mortality occurs from this disease. Morbidity occurs from progressive contraction of the affected digits, resulting in both cosmetic and functional disability. With severe flexion deformity, the nail of the affected digit may penetrate the palmar skin. Infection secondary to this trauma has been reported.

Race

Most patients appear to be of Northern European descent, especially Scotland and the Scandinavian countries. The disease is less likely to occur in African and Asian populations. Case reports and series have shown that persons of any race can be affected.⁴

Sex

All studies show a male preponderance earlier in life, with men presenting for treatment in the fifth decade and women presenting a decade later. Typical male-to-female ratios of 3-9:1 have been reported. By the ninth decade of life, no sexual difference in incidence is found. Men are more likely than women to undergo surgery for the disease.

Age

The average age of onset in men is in the sixth decade, with onset occurring later in women, in the seventh decade. Dupuytren contracture has been reported in children and infants⁵ but is considered rare.

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