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Disease Development

 

     

 

WHAT CAUSES DUPUYTREN'S DISEASE AND CONTRACTURE?

Unfortunately, although extensive research has been conducted the exact cause of the disease still remains elusive. We know there is a strong genetic component to the disease and there are many conditions and factors associated with the disease's presentation. However, no clear cause and effect associations have been established.

 


ASSOCIATED CONDITIONS & FACTORS

Genes

Dupuytren's disease is most common in white males of Northern European descent. It is uncommon in blacks, and in blacks is more often associated with a history of trauma. A US Veterans study gave this racial breakdown: the incidence of Dupuytren's in their study was Caucasian: 0.7%; Hispanic: 0.2%; Black: 0.1%; Native American: 0.1%; Asian: 0.07%. Dupuytren's is six times more common in men than women. Women develop the disease on the average ten years later than men. The disease appears to run in families, and often follows an autosomal dominant inheritance. Dupuytren's contracture has been reported in in 21% of women and 39% of men over the age of 60 in North-east Scotland. Even with a genetic predisposition, presentation is variable, and identical twins with Dupuytrens do not necessarily have identical disease. There are genetic differences between patients with and without Dupuytren's. Although a genetic pattern of HLA DR antigens have been reported in both Dupuytren's and scleroderma, a "Dupuytren's gene" has not been identified.

Age    

Increasing age increases the risk of developing Dupuytren's. Although reported in infants, children, and teenagers, this is rare. Other childhood conditions may mimic Dupuytren's, such as the benign recurring digital fibroma of childhood or malignant epithelioid sarcoma. In Iceland, where it is common, Dupuytren's in men found in 7% in the age group 45-49 years, 40% in those 70-74 years old. In Norway, 30% of the population over 60 has Dupuytren's.

Diabetes

There is a five to ten times increased risk for diabetics to develop Dupuytren's contracture, related to the duration, presence of diabetic retinopathy, but not severity of the diabetes.  In diabetics, Dupuytren's is often a less aggressive form, but the radial hand is more often involved.

 
Diabetic Limited Joint Mobility Syndrome   

Patients with this syndrome are twice as likely to have Dupuytren's than with diabetes alone, and it relates to the duration of diabetes. The relationship may be explained by smoking, which predisposes to both conditions

Smoking

Smokers have increased risk. Twice the risk of nonsmokers

Alcoholism

Increased, although some surveys dispute this.  The association may instead be with smoking or hyperlipidemia associated with alcoholism, or alcoholic liver disease. Alcoholic liver disease is a risk factor,  nonalcoholic liver disease is not, although this is also disputed.

Thyroid disorders
   
Increased incidence, more for hypothyroidism than hyperthyroidism

Stretching
   
Contrary to natural instinct, the act of stretching the skin of the palm appears to aggravate or provoke Dupuytren's contracture.

Frozen Shoulder

50% chance of developing Dupuytren's, even more common with diabetes

Peyronie's Disease

15 - 25% incidence, 80% in familial forms of Peyronie's.

Lederhosen Disease

28% chance of having Dupuytren's

Rheumatoid Arthritis

Lower chance of developing Dupuytren's, but when present, requires special surgical planning

Trauma

Dupuytren's may develop after hand trauma, particularly after Colles' wrist fracture (distal radius fracture). One study reported a 40% incidence of Dupuytrens 18 months after Colles' fracture. Duputren's developing after surgery has also been reported.

Hyperlipidemia

Increased

Vibration exposure

Increased with vibration exposure, Patients with vibration white finger syndrome are two times as likely to have Dupuytren's.

Epilepsy

When present, Dupuytrens appears to have a more aggressive character, although conflicting reports exist. Association may be due to  phenobarbitone  medication rather than epilepsy itself, although this is debatable as well. There may be an association between Dupuytren's, RSD and antiepileptic drugs.

Gout

No effect.

Glucosamine / Chondroitin Sulfate
   
Glucosamine / Chondroitin sulfate preparations are available as nutritional supplements with claims of improving joint function. Although no cause and effect relationship has been established, chondroitin sulfate and glycosaminoglycan levels are elevated in the tissues affected by Dupuytren's contracture.

Growth hormone therapy
   
Possibly

Arcus senilis

Increased incidence, possibly due to mutual association with hyperlipidemia

Reflex Sympathetic Dystrophy

RSD after wrist fracture triples the risk of developing Dupuytren's compared to no RSD. There may be an association between Dupuytren's, RSD and antiepileptic drugs. More common postop in women and possibly related to psychological factors. There may be an association between Dupuytren's, thoracic outlet fibrosis and reflex sympathetic dystrophy

Hemodialysis

Increased, although many factors may be at play

Palmaris longus

Increased risk if this tendon is present in the wrist. Excision of the palmaris longus tendon has been reported to reduce recurrence

Increased serum IgA

Increased risk

Vascular insufficiency

Increased risk

Manual Labor

Increased risk, although controversial. Vibration exposure is a risk factor

Carpal tunnel syndrome

   
Although postoperative flare has been reported as more common with simultaneous fasciectomy and carpal tunnel release, contrary reports exist.

Vinyl Chloride

HLA DR antigens have been identified both in Dupuytren's patients and in patients with vinyl chloride exposure related scleroderma. An increased incidence of  Dupuytren's was reported at a polyvinyl chloride (PVC) manufacturing plant in workers who handled the product extensively.

HIV infection
   
Increased risk debated

 


DUPUYTREN'S MAY CAUSE INCREASED RISK OF HAVING OTHER CONDITIONS

Diabetes

    Increased

Hyperlipidemia

    Increased: present over half the time

Psychological problems

    No association

Malignancy

    Increased sarcoma, cancer, possibly due to mutual association with smoking and alcohol abuse.

Mortality

    Increased, especially when presenting under 60 years old

Ulnar neuropathy

    Increased

Cold induced vasospasm


    Increased

Thin (low triceps skin fold thickness)

    More likely to be thin? associated with smoking

     

  BASIC SCIENCE FINDINGS

  • The balance between certain enzymes (matrix metalloproteinases, fibrinolysins, plasminogen activators) and their natural inhibitors is disturbed in patients with active Dupuytren's disease, and may be affected by tension on the affected tissues.

  • The cells in the cords of Dupuytren's disease are unusually sensitive to the effects of "growth factors", normal body chemicals involved in wound healing. These include transforming growth factor beta 1 (TGF-beta(1), transforming growth factor beta 2 (TGF-beta(2), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF) and othersThe process may be triggered by a combination of mechanical stress and either TGF-beta, or PDGF.

  • Dupuytren's cords have unusually high levels of the protein tyrosine phosphorylated beta-catenin, and the cells have higher than normal levels of the substance alpha smooth muscle actin and the enzyme lysyl oxydase.

  • Cell-matrix interaction abnormalities, stimulating contraction. A three dimensional mesh of actin microfilaments (the "fibronexus") links cells to each other and to the extracellular matrix, which, in Dupuytren's disease, contains unusually high levels of fibronectin.

  • Abnormal androgen receptors have been implicated in the abnormal tissue, although not by all investigators.

  • Low oxygen levels resulting in reactive forms of oxygen (superoxide free radicals, oxygen free radicals) due to poor circulation have been implicated, possibly due to activation of the enzyme xanthine oxidase. The blood clotting system may be triggered by production of high level of plasminogen activator. Microvascular circulatory changes develop, with narrowing and blockage of capillaries microscopic hemorrhage and other changes in the blood vessel walls. This might explain the relationship of smoking to Dupuytren's. Miroculatory changes may arise from abnormal regulatory nerves in the fascia itself. Nodules show near complete absence of blood vessels, and other studies show evidence of low oxygen levels in the diseased tissues.

  • T-cell and B-cell Immune mechanisms, autoantibodies to collagen or other immune mechanisms may be involved.

  • Genetic variations have been demonstrated in nodules, in the form of recurrent clonal numerical abnormalities.

  • The contraction is due to a mechanism also seen in other contracting tissues such as healing wounds and some types of cancers. Dupuytren's fibroblasts can acquire smooth muscle characteristics and are then able to contract. These modified fibroblasts are called myofibroblasts, and are found in nodules, but not cords. In diffuse disease, these changes can affect cells in the skin as well as the fascia. Myofibroblasts contract through an interaction of myofilaments and the enzyme ATPase within their cell bodies, and the extent of recurrence after surgery correlates with myofibroblast activity at the time of surgery.

  • Certain nerve endings (Pacinian corpuscles) are enlarged and surrounded by fibrous tissue in affected areas.

  • Overall collagen metabolism may be disturbed in patients with Dupuytren's. Type III collagen is increased in Dupuytren's cords.

  • Mechanical tension forces or stretching the affected area may provoke contracture, possibly by stimulating changes in the microcirculation. Dynamic physical forces may produce biochemical changes through changes in tissue electrical fields.  Paradoxically, continuous tension on the tissues causes a temporary reversal of the process, probably by stimulating enzymes involved in tissue remodeling. One hypothesis is that loss of normal gliding motion between layers of fascia results in abnormal tissue tension which provokes the contracture process.

 

 Last updated 10.8.08

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