A Primary Care Perspective on Keloids

Steven Davidson, MD, DDS; Nasir Aziz, MD, MA, PGY-1; Rashid M. Rashid, MD, PhD, PGY-2; Amor Khachemoune, MD, CWS

Disclosures

Medscape J Med. 2009;11(1):18 

In This Article

Pathogenesis

As mentioned earlier, the cause of keloid formation is still not understood, and several theories have been proposed. A few are reviewed below.

Keloids result from excess scar tissue secondary to increased growth factor activity and alterations in the extracellular matrix. Keloid fibroblasts are known to have a heightened sensitivity to tumor growth factor (TGF)-beta, which is normally produced during the proliferative phase of wound healing.[15,16] Similarly, keloid fibroblasts have a 4- to 5-fold increased level of platelet-derived growth factor receptor, which results in a synergistic growth-stimulator effect with TGF-beta.[17]

Also, the extracellular matrix that regulates growth factors is abnormal. Keloids often have elevated levels of fibronectin and certain proteoglycans as well as decreased levels of hyaluronic acid.[18] Fibronectin and hyaluronic acid are proteins expressed during normal wound healing, and their dysregulation contributes to the fibrotic phenotype seen in keloids.[19,20]

Abnormal regulation of the collagen equilibrium leads to the characteristic appearance of a keloid because the collagen content is higher than in normal tissue or scar tissue.[2,8] Although the collagen is disorganized with thicker and wavier bundles, the hallmark of the keloid structure is the "collagen nodules" present at the microstructural level.[21] Also, the ratio of type I to type III collagen is significantly increased in keloids due to alterations at the pretranscriptional and posttranscriptional levels.[12]

Collagen is mainly produced by fibroblasts and to some extent endothelial cells.[7,21,22] Keloid fibroblasts have a greater capacity to proliferate because of a lower threshold to enter the S phase of mitosis, resulting in greater autonomous production of collagen.[3,18,22,23] The collagen produced by fibroblasts is normally degraded by the enzyme collagenase synthesized by fibroblasts and inflammatory cells.[21,22] Enzymes that inhibit or degrade collagenase exert an additional level of collagen regulation.[22,24] Concentrations of collagenase inhibitors, namely alpha-globulins and plasminogen activator inhibitor-1, are consistently elevated in both in vitro and in vivo keloid samples, whereas levels of degradative enzymes are frequently decreased.[22,24]

An inherited abnormal immune response to dermal injury may cause keloid formation, as these lesions are associated with particular human leukocyte antigen subtypes. Studies suggest an association between group A blood type and human leukocyte antigen B14, 21, BW35, DR5, and DQW3 in patients with a keloid diathesis.[25] Patients who develop keloids have a disproportionately high incidence of allergic diatheses and elevated levels of serum immunoglobulin E.[26] Multiple reports have found patterns in the serum complement, immunoglobulin G, and immunoglobulin M levels in patients with keloids, suggesting a systemic immune state genetically predisposed to keloid formation.[27,28] In this way, keloid formation could be considered an autoimmune connective tissue disease.

According to the sebum reaction theory, keloids arise from an immune reaction to sebum. Dermal injury exposes the pilosebaceous unit to the systemic circulation, initiating a cell-mediated immune response in persons who retain T lymphocytes sensitive to sebum. Subsequent release of cytokines, including various interleukins and TGF-beta, stimulates chemotaxis of mast cells and production of collagen by fibroblasts. As the keloid expands, further pilosebaceous units on the advancing border are disrupted, leading to further propagation.[29,30] Keloids preferentially occur in areas with a high concentration of sebaceous glands, including the chest wall, shoulder, and pubic area, while rarely occurring in areas relatively devoid of sebaceous glands, such as the palms and soles. Because humans are the only mammals with true sebaceous glands, the sebum reaction hypothesis partly explains why keloids only occur in humans.

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