| Necrobiosis lipoidica | |
|---|---|
| Other names | Necrobiosis lipoidica diabeticorum |
 | |
| Specialty | Dermatology  |
Necrobiosis Lipoidica is a rare, chronicskin condition predominantly associated withdiabetes mellitus (known asnecrobiosis lipoidica diabeticorum orNLD). It can occur in individuals withrheumatoid arthritis or without any underlying conditions (idiopathic) and can also be displayed in patients withobesity,hypertension,celiac disease, andmetabolic syndrome. About a quarter of Necrobiosis Lipoidica is associated with diabetes mellitus.
The broader overarching definition ofnecrobiosis is a gradual physiological death of a cell. It can be caused by basophilia, erythema, or a tumor. As a dermapathology term, it refers to altered collagen or altered dermal connective tissue. Necrobiosis Lipoidica is linked tomicrovascular damage and collagen degeneration. The exact cause of this condition is not known, but it involvescollagen degeneration and agranulomatous response in the layer of the skin called thedermis, often affecting the deeper fat layer and thickening dermal blood vessels.
It is characterized by hardened, raised areas of the skin, often appearing on the shins, with a yellowish center and a surrounding dark pink area. The lesions are generally asymptomatic but can become tender andulcerate when injured. Histological features and skin changes are caused by thickening of blood vessel wall,collagen deterioration,granuloma (clustered white blood cells in tissues) formation and fat deposit. Necrobiosis Lipoidica has many possible contributing factors and research for treatment and causes is an ongoing process.
Necrobiosis Lipoidica is known to have a strong correlation with diabetes mellitus. It occurs after diabetes mellitus is diagnosed in 64% of cases. Although there is no conclusive association between the two.[1] NL may present itself in a completely healthy individual. It is also found othermetabolic diseases,thyroid disorders, and inflammatory diseases. It is found predominantly in females 3:1 comparative to males.[2] Onset of NL typically occurs at ages 30-50 but is not exclusively linked to this range.[1] A few studies have found thatulceration is most common in male patients with diabetes mellitus.[3]
It affects approximately 0.3%- 1.2% of diabetics, showing a higher prevalence in women.[4] There are many factors involved in Necrobiosis Lipoidica. A common theory for why it is associated with diabetes is a result of vascular disturbance involvingimmune complex deposition that leads to collagen degeneration.[5] The core pathologies of diabetes include thickening of thebasement membrane, loss ofpericytes,endothelial dysfunction and capillaryocclusion.[6] Since NL is more common in patients with diabetes, there is a suggested link with the microvascular damage associated with diabetes, where the small blood vessels in the skin are impacted.
Immunoglobulins (IgM, IgA),complement (C3) and fibrinogen have been found in blood vessel walls of patients with NL. Both Immunoglobulin and C3 are known to play a significant role in the immune response.Fibrinogen is a protein that plays a crucial role in blood clotting (often found at the dermal- epidermal junction). These deposits cause vascular thickening, which is a hallmark of NL.[7]
Abnormal collagenfibrils are often found in diabetes. Due to increased levels oflysyl oxidase, collagen increases cross-linking. This thickens the basement membrane, another hallmark of NL.[8]
Impairedneutrophil migration (caused by genetic defects, infections, and the aging process) causes increased macrophage activity that can lead to granuloma formation, a hallmark of NL. Furthermore,TNF-α is a pro-inflammatory cytokine that's activated bymacrophages, and it plays a critical role in granuloma formation.[10]
Tissue Architecture in NL Lesions
Alesion is a tissue that has been altered or injured. They can occur as wounds or in the case of progressive NL, ulcers.
The tissue architecture of NL is characterized by degeneration of collagen in thedermis andsubcutaneous layers. The lesions exhibit granulomatous inflammations, palisading granulomas, and thickened blood vessels. Palisading granulomas are significant because they show an immune cell ring around degenerated tissue, commonly seen inautoimmune and chronicinflammatory diseases. Thickened blood vessels are a result of immune cell accumulation. Together, all of these structural features indicate NL as a chronic, inflammatory response. Fibroblasts and endothelial cells are malfunctioning, and there is an imbalance in tissuehomeostasis.[11]
Fibroblast and collagen remodeling
Fibroblasts contribute to the formation of connective tissue, collagen and elastin. Failure in fibroblasts causes skin toatrophy and degenerate.
Increased uptake ofGLUT-1 (a glucose transporter) is observed in NL cases. When up-regulated:glycolysis,oxidative stress, and fibroblastproliferation all increase. Despite the metabolic increase, fibroblasts in NL dysfunction. This suggests in NL tissue decay and dysfunction is linked to both structural and immunological tissue components. The tissue is observed to have increased GLUT-1 and decreased pro collagen mRNA.[12]
A predominance ofType 1 collagen is observed in PL. Type 1 is associated with early phase wound healing compared toType 3 collagen seen in normal, healthy tissues.[13]
An upregulation of vascular cell adhesion molecule-1 is observed in NL tissue, indicating leukocyte aggregation and an inflammatory response. Furthermore, there is a reducedVGEF expression along with AGE-mediatedcross-linking, reducing ECM fluidity. Both factors impair new vessel growth, lead to poor oxygenation, and impair tissue healing.[14]
Macrophages present in the lesion environment differentiate intoMultinucleated Giant Cells after prolonged activation. Secretedmatrix metalloproteinases degrade collagen and fuel necrobiosis in response to immune activation.T cells, prominent in NL (Th-1 type cytokines) inhibit healing by the production ofIFN-γ, suppressing M2 repair.[15] These factors suggest a link to autoimmune conditions, as these factors explain a pro-inflammatory feedback loop.
Necrobiosis, mainly affectingdermis andsubcutaneous tissue, can also impact theepidermis.TNF-α andIFN-γ impair keratinocyte function, inhibiting keratinocyte proliferation and migration, two processes essential for reepithelialization and wound closure. Chronickeratinocyte dysfunction can lead to tissue atrophy. Furthermore, inflammatory signaling maydownregulate key cell-cell adhesion molecules such asE-cadherin andβ-catenin compromising epidermal tight junctions and leading to barrier dysfunction. All of these factors impact the epidermal integrity and barrier.[16]
Oxidative stress causes the accumulation of reactive oxygen species (ROS), resulting in oxidative damage to DNA, damage to proteins involved in cellular repair, and damage to lipids that support the skin barrier. Oxidative stress can hinder the fibroblasts' collagen production, endothelial cellangiogenesis, and keratinocytes're-epithelialization. The result of oxidative stress is a state of cellular senescence, where cells secrete pro-inflammatory factors and cannot divide. Senescent cells signal to immune cells, perpetuating a non-resolving wound that can develop into an ulcer.[17]
As Necrobiosis Lipoidica has a common co-occurrence in Type 1 diabetes, metabolic dysregulation found in diabetes has a profound impact on cellular function.Diabetes is known to alter the expression ofmiRNAs and promote oxidative stress. Prolonged high blood sugar can increase oxidative stress, disruptnitric oxide production, essential forvasodilation and vessel formation.[10]
Hyperglycemia also leads to the accumulation ofadvanced glycation end-products (AGEs), which activate the RAGE–NF-κB axis, leading to inflammation and endothelialapoptosis. Structural changes occur, including basement membrane thickening and extracellular matrix stiffening.
NL/NLD most frequently appears on the patient's shins, often on both legs,[18] although it may also occur on forearms, hands, trunk, and, rarely,nipple,penis, and surgical sites. The lesions are oftenasymptomatic, but may become tender and ulcerate when injured. The first symptom of NL is often a "bruised" appearance (erythema) that is not necessarily associated with a known injury. The extent to which NL is inherited is unknown.[19]
NLD appears as a hardened, raised area of the skin. The center of the affected area usually has a yellowish tint, while the area surrounding it is a dark pink. The affected area can spread or turn into an open sore. When this happens, the patient is at greater risk of developingulcers. If an injury to the skin occurs on the affected area, it may not heal properly, or it will leave a dark scar.[20]
Although the exact cause of this condition is not known, it is an inflammatory disorder characterized bycollagen degeneration, combined with agranulomatous response. It always involves thedermis diffusely, and sometimes also involves the deeper fat layer. Commonly, dermal blood vessels are thickened (Microangiopathy).[21]
It can be precipitated by local trauma, though it often occurs without any injury.[22]
As a metabolically driven skin disorder, the pathology is characterized by poor intracellular glucoseutilization leading to metabolically stressedfibroblasts. Despite an increasedGLUT-1 response,fibroblasts in NL fail to produce normal collagen, weakening and breaking down the skin's structure. Vascular impairments reduce oxygen and nutrient circulation, creating hypoxia and tissue breakdown.
NL is diagnosed by askin biopsy, demonstrating superficial and deepperivascular and interstitial mixed inflammatory cell infiltrate (includinglymphocytes, plasma cells, mononucleated and multinucleatedhistocytes, andeosinophils) in the dermis and subcutis, as well as necrotising vasculitis with adjacentnecrobiosis and necrosis of adnexal structures.[23] Areas of necrobiosis are often more extensive and less well defined than ingranuloma annulare. The presence of lipid in necrobiotic areas may be demonstrated bySudan stains.Cholesterol clefts, fibrin, andmucin may also be present in areas of necrobiosis. Depending on the severity of the necrobiosis, certain cell types may be more predominant. When a lesion is in its early stages, neutrophils may be present, whereas in later stages of development, lymphocytes and histiocytes may be predominant.[24]
There is no clearly defined cure for necrobiosis.[25] NLD may be treated withPUVA therapyPhotodynamic therapy and improved therapeutic control.[26]
Although there are some techniques that can be used to diminish the signs of necrobiosis, such as low-doseaspirin orally, asteroid cream or injection into the affected area, this process may be effective for only a small percentage of those treated.
First medications applied are topical corticosteroids, but these may not be effective for all patients. Compression therapy and proper wound care are essential for treatment.[27]
Anti-inflammatory,immunosuppressive, andimmunomodulatory agents like chloroquine, dapsone, and oral calcineurin inhibitors.[28] These target the cyclic and damaging immune response occurring in NL.[29]
Since TNF is essential to granuloma formation. Antibodies that bind to TNF-α to prevent its action are helpful for reducing inflammation, pain, and the growth of ulcers. A study found a 70% complete reduction of NL when usingTNF-α inhibitors.[30]
Hyperbaric oxygen can also be used to increase the amount of oxygen circulation and promote wound healing.[31]
Necrobiosis Lipoidica is classically chronic, difficult to manage, and treat. The prognosis is not reassuring.Squamous cell carcinoma is often a concern with NL. However, this occurs very late into the diagnosis[32]
Treatment can typically stop the growth of lesions and ulcers. Lesion treatment is often very painful and requires intensive wound care. Aesthetically, wounds rarely heal without scarring.[33]