黄褐斑的最新进展（中）

黄褐斑的分类

表1为黄褐斑传统分类法，该法以黑色素的深度为依据，有助于预测其治疗效果。然而，Wood灯检查未必能精确的测定黑色素的深度。因此，基于Wood灯检查与基于组织病理学的分类，两者相关性较差[图3]。

Table 1: Classification of melasma based on the depth of melanin pigment

表1：基于黑色素深度的黄褐斑分类

Figure 3: H and E, ×200 epidermis shows increased melanin concentrationin basal keratinocytes and underlying solar elastosis along with dermalmelanophages (Courtesy of Dr. Uday Khopkar, Mumbai, India)

图3：基底层角质细胞的黑色素浓度增高，日光性弹性组织变性伴真皮嗜黑素细胞（H&E，×200）（印度孟买Uday Khopka博士提供）

皮肤镜检可用于黄褐斑的诊断。皮损为不同形态的褐色弥漫性网状色素沉着，散在毛囊开口。图4-9为表皮黄褐斑患者的皮肤镜下所见。真皮黄褐斑为弥漫性暗棕色至浅灰色假性网状色素沉着，可见环状、蜂巢状和弓状结构。

Figure 4: Dermoscopy from left cheek melasma showing dispersed brownish spots. White hairs are due to bleaching

图4：左脸颊黄褐斑皮肤镜示散在性褐色斑点。白色头发是由于漂白药物所致。

Figure 5: Dermoscopy from right cheek melasma showing dispersed brownish spots

图5：右脸颊黄褐斑皮肤镜示散在性褐色斑点。

Figure 6:Dermoscopy from right cheek melasma showing dispersed pigment and depigmentation

图6：右脸颊黄褐斑皮肤镜示散在性色素沉着和色素减退。

Figure 7: Dermoscopy from nasal melasma showing larger dispersed brownish spots

图7：鼻部黄褐斑皮肤镜示大的散在性褐色斑点。

Figure 8: Dermoscopy from the surrounding skin revealing more steroid induced telangiectasias

图8：周围皮肤皮肤镜示由类固醇所致的毛细血管扩张。

Figure 9: Dermoscopy from surrounding normal skin revealing mild steroid abuse-induced telangiectasias

图9：周围正常皮肤皮肤镜示由轻度滥用类固醇引起的毛细血管扩张。

反射式共聚焦显微镜（RCM）是一种用于评估皮肤深达真皮乳头层病灶的一种无创工具。该项技术可以提供与组织病理学检查相匹配的高分辨率的实时正面图像。Kang等人进行了一项研究以调查RCM在黄褐斑的应用，且提供了一组与组织学相关的形态学标准。如图10-11、表2所示。

Figure 10: Confocal microscope images of melasma showing epidermal pigmentation: (a) Melasma on the cheek. L is for lesional skin and N is for normal perilesional skin. (b) Confocal images depict cobblestoning and loss of dermal papillary rings at the basal layer of the melasma lesion (L) compared to perlesional normal skin (N). Scale bar: 50 um. (c) Histopathology from same lesion showing greater epidermal hyperpigmentation and flattened rete ridges in lesion compared to perilesional normal skin Fontana-Masson staining, horizontal line indicates where reflectance confocal microscopy image is taken from (source acknowledged: Kang HY, Bahadoran P, Ortonne JP. Reflectance confocal microscopy for pigmentary disorders. Exp Dermatol 2010;19:233-9)

图10：黄褐斑的共聚焦显微镜图像检查示表皮色素沉着：（a）脸颊黄褐斑。L表示皮损，N表示皮损周围正常皮肤。（b）共聚焦图像显示与皮损周围正常皮肤（N）相比，黄褐斑皮损（L）色素性基底样细胞呈鹅卵石样，其基底层真皮乳头环缺失。比例尺：50um。（c）同一处皮损的组织病理学显示与皮损周围正常皮肤相比，皮损处表皮色素沉着过度，且表皮突扁平。（Fontana-Masson染色，横线表明共聚焦显微镜图像的出处）（来源：Kang HY， Bahadoran P，Ortonne JP. Reflectance confocal microscopy for pigmentary disorders. Exp Dermatol 2010;19:233-9）

Figure 11: Confocal microscopy image of melasma showing dermal pigmentation: (a) Clinical picture of melasma. (b) Confocal microscopy showing bright plump cells in dermis. (c) Histopathology picture showing melanophages in the dermis (source acknowledged: Kang HY, Bahadoran P, Ortonne JP. Reflectance confocal microscopy for pigmentary disorders. Exp Dermatol 2010;19:233-9)

图11：黄褐斑的共聚焦显微镜图像显示真皮色素沉着：（a）黄褐斑的临床图片。（b）共聚焦显微镜图像显示真皮层见明亮饱满的细胞。（c）组织病理图像显示真皮层噬黑素细胞。（来源：Kang HY， Bahadoran P，Ortonne JP. Reflectance confocal microscopy for pigmentary disorders. Exp Dermatol 2010;19:233-9）

Table 2: Morphological criteria along with histological correlation seen in patients with melasma using RCM

RCM: Reflectance confocal microscopy

表2：黄褐斑患者应用RCM显示其形态学标准与组织学具有相关性

RCM：反射式共聚焦显微镜

RCM显示日光性弹性组织变性显著，真皮层血管增生。此外不同区域及其区域内部的噬黑素细胞局部分布不一。RCM提供了一种依据色素变化分类黄褐斑的新方法，这有助于改善黄褐斑的预后及监测患者治疗黄褐斑的疗效。

治疗方法

HQ在现代治疗中的作用

HQ是一种二羟基苯酚，可以通过抑制酪氨酸酶抑制二羟基苯丙氨酸转化为黑色素。其他作用机制包括抑制RNA和脱氧核糖核酸的合成，破坏黑素细胞。

HQ被认为是治疗黄褐斑的金标准(2-4%)。联合其他药物时，其疗效增强。联合药物包括Kligman配方（5％HQ，0.1％维甲酸和0.1％地塞米松），改良的Kligman配方（4％HQ，0.05％维甲酸和1％氢化可的松醋酸酯），Pathak配方（2％HQ和0.05-0.1％维甲酸）和Westerhof配方（4.7％N-乙酰半胱氨酸，2％HQ和0.1％曲安奈德）。同样也已尝试了联合4％HQ微胶囊剂、0.15％视黄醇和抗氧化剂治疗黄褐斑，研究显示其对疾病严重程度、色素沉着强度、皮损面积和比色法评估均有所改善。

在一项随机的，左右面部比较的研究中，Monheit 和 Dreher比较了20名黄褐斑白人女性患者应用美白霜（含4％HQ和4倍美白活性物质）与TCC（含4％HQ、0.05％维甲酸以及0.01％肤轻松）的安全性和疗效。治疗四周后（1次/日），美白霜SLC与成熟的TCC在治疗黄褐斑的安全性和疗效相当。三分之一的患者使用两种霜剂后出现局部红斑、皮肤干燥脱屑。

Arellano等人在一项随机对照研究中，对242名巴西和墨西哥中度至重度黄褐斑患者，在应用两种3重联合霜剂（含HQ，肤轻松和维A酸）6个月，比较其临床安全性和疗效。根据全球严重程度评分，黄褐斑面积严重程度指数（MASI），以及生活质量的问卷调查来评估疗效。每日应用TCC8周后，受试者被随机分配接受TCC（2次/周），或者逐渐减少剂量（3次/周[第1个月]，2次/周[第2个月]，1次/周[第4个月]），为期6个月。研究发现每周两次的治疗方案对重症黄褐斑患者来说，延缓复发的效果更佳。约53%患者6个月后无复发。

氨甲环酸

氨甲环酸（TA）是一种反式-4-（氨甲基）环己烷羧酸，作为抗纤维蛋白溶解制使用超过30年的赖氨酸类似药物。通过阻碍血纤维蛋白溶酶原与角质形成细胞结合，抑制了UV诱导的角质形成细胞中血纤维蛋白溶酶的活性。导致产生游离的花生四烯酸较少，产生前列腺素能力减弱，从而降低了黑素细胞酪氨酸酶的活性。Zhang等人证实TA可以干扰酪氨酸酶的催化反应并抑制黑素生成。治疗黄褐斑时，TA可以口服，外用或皮内注射。TA作为止血剂时规定剂量1000 mg，3次/日，然而在治疗黄褐斑时，其剂量为250 mg，2次/日。

Wu等人的研究中，给予74名黄褐斑中国患者TA 250 mg，2次/日，持续6个月。通过两名医师根据患者黄褐斑尺寸的减小和色素沉着的改善来评估治疗效果。10.8%的患者疗效非常好，54%很好，31.1%一般，4.1%差。副作用为胃肠道不适及月经过少。9.5%的患者复发。

TA也可外用。最近Kanechorn等人实施的双盲随机性前瞻研究中，采用基质对照，给23名双侧面部黄褐斑亚洲患者使用5％TA脂质体凝胶制剂，持续12周，进行的左右面部比较试验。78.2%患者应用TA后黑色素指数减少。然而，与基质相比，疗效并不显著。这项研究还发现局部使用TA可引起红斑。

Lee的一项研究中，给100名黄褐斑韩国患者皮内注射TA（4 mg/ml，1次/周），持续12周。发现MASI评分显著减少（8周时，13.22降至9.02， vs.12周时再降至7.57，P <>

TA的优势是具有良好的安全性。此外，温度稳定，对UV不敏感，且不易氧化，因此可用于SLCs。需要进一步研究来评估其抗黄褐斑的潜力。

4-正丁基间苯二酚

4-正丁基间苯二酚是间苯二酚的一种衍生物，可抑制酪氨酸酶和酪氨酸酶相关蛋白，以及黑色素生物合成途径中的酶。研究显示其对黄褐斑患者具有良好疗效和安全性。

Huh等人进行的随机对照左右面部的试验中，评估了23名黄褐斑患者使用0.1%4-正丁基间苯二酚脂质体乳霜的疗效和安全性。研究发现进行治疗的那面脸部的黑素指数显著减少（P <>

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Classification of melasma

Table 1 shows the traditional classification being used for melasma. It is based on the depth of melanin pigment and helps in predicting the therapeutic outcome. However, Wood's light examination may not be accurate in determining the depth of pigment. There is poor correlation between the classification based on Wood's light examination and histopathology [Figure 3].

Dermoscopy can be used for the diagnosis of melasma. Lesions of melasma show diffuse reticular pigmentation in various shades of brown with sparing of follicular openings. Figures 4-9 depict the dermoscopic appearance of a patient with epidermal melasma. Dermal melasma shows diffuse dark brown to grayish pseudoreticular pigmentation. Annular, honeycomb and arcuate structures may be seen.

Reflectance confocal microscopy (RCM) is a noninvasive tool for the evaluation of the skin up to the papillary dermis. This technique can provide real-time en face images that have a resolution that matches that of histopathological examination. Kang et al. carried out a study to investigate the role of RCM in melasma and provide a set of morphological criteria with histological correlations. These are depicted in Figures 10 and 11. These are shown in Table 2.

RCM showed significant solar elastosis and increase of blood vessels in the dermis. It was also seen that the topographic distribution of melanophages was heterogenous within and among different regions. RCM offers an innovative way of classifying melasma by pigment changes. This can help us in refining the prognosis of melasma. It can also help in monitoring response to therapy.

THERAPEUTIC MODALITIES

Current role of HQ

HQ is a dihydric phenol that inhibits the conversion of dopa to melanin by inhibiting the tyrosinase enzyme. Other proposed mechanisms of action include the inhibition of RNA and deoxyribonucleic acid synthesis and destruction of melanocytes.

HQ is considered the gold standard of treatment for melasma. It is used at a concentration of 2-4%. Its efficacy is enhanced when used in combination with other agents. These combinations include the Kligman formula (5% HQ, 0.1% tretinoin, and 0.1% dexamethasone), modified Kligman’s formula (4% HQ, 0.05% tretinoin and 1% hydrocortisone acetate), Pathak’s (2% HQ and 0.05-0.1% tretinoin) and Westerhof’s formula (4.7% N-acetylcysteine, 2% HQ and 0.1% triamcinolone acetonide). Combination of microencapsulated HQ 4% with retinol 0.15% and antioxidants has also been tried in melasma with studies showing improvement in disease severity, pigmentation intensity, lesion area and colorimetry assessments.

In a randomized, split-face study, Monheit and Dreher compared the safety and efficacy of skin lightening cream (containing HQ 4% and four skin brightening actives) with a TCC (containing 4% HQ, 0.05% tretinoin, and 0.01% fluocinolone acetonide) in 20 Caucasian female patients with melasma. They found that after 4 weeks once daily treatment, the skin lightening cream SLC was comparable in both efficacy and safety to the well-established TCC treatment for melasma. One-third of patients experienced local side effects in the form of erythema, peeling of skin and dryness with both the creams.

In a randomized, controlled study Arellano et al. compared the clinical efficacy and safety of two 6-month triple combination (containing HQ, fluocinolone acetonide and tretinoin) maintenance regimens in 242 Brazilian and Mexican patients with moderate-to-severe melasma. Global severity score, melasma area severity index (MASI), and quality of life questionnaire were used to assess the efficacy of treatment. After eight weeks of daily TCC application, subjects were randomized to receive TCC in a twice weekly or tapering regimen (3/week [1st month], 2/week [2nd month], 1/week [4th month]) for 6 months. They found that twice-weekly regimen showed better effectiveness on postponing relapse in patients with severe melasma. About 53% of patients were relapse-free after 6 months.

Tranexamic acid

Tranexamic Acid (TA) is trans-4-(aminomethyl) cyclohexane carboxylic acid, a lysine analog that is in use as an antifibrinolytic agent for over 30 years. It inhibits UV-induced plasmin activity in keratinocytes by preventing the binding of plasminogen to the keratinocytes.This results in less free arachidonic acid and a diminished ability to produce prostaglandins, and this decreases melanocyte tyrosinase activity. Zhang et al. demonstrated that TA can interfere with the catalytic reaction of tyrosinase and inhibit melanogenesis. In the treatment of melasma, TA can be used orally, topically or by intradermal microinjection. As a hemostatic, TA is prescribed in a dose of 1000 mg 3 times daily, whereas in the treatment of melasma, it is used in a dose of 250 mg twice daily.

In a study conducted by Wu et al., 74 Chinese patients with melasma were treated with TA 250 mg twice daily for 6 months. The effects of treatment were evaluated by two physicians and by the patients based on the reduction in melasma size and improvement of pigmentation. The results were excellent in 10.8%, good in 54%, fair in 31.1% and poor in 4.1%. Side effects seen were gastrointestinal discomfort and hypomenorrhea. Recurrence was seen in 9.5% patients.

TA can also be used topically. In a recent double-blind randomized prospective study by Kanechorn et al., 5% TA incorporated in a liposome gel formulation was used in 23 Asian women with bilateral epidermal melasma. The treatment was given for 12 weeks and compared with the vehicle in a split-face trial. 78.2% of patients showed a decrease in the melanin index. However, results were not significant as compared with vehicle. Another finding seen in this study was the erythema induced by topical TA.

In a study conducted by Lee et al. in 100 Korean women with melasma, TA was used intradermally (4 mg/ml) every week for 12 weeks. The treatment caused a significant decrease in MASI score (13.22 vs. 9.02 at week 8 and vs. 7.57 at week 12, P < 0.05="" for="" both)="" with="" minimal="" side="" effects.="">

The advantage with TA is its good safety profile. Furthermore, it is temperature stable, UV insensitive and does not get oxidized easily, hence it can be used in SLCs. More studies are needed to evaluate its anti-melasma potential.

4-n-Butylresorcinol

It is a derivative of resorcinol that inhibits tyrosinase and tyrosinase related protein, enzymes in the melanin biosynthetic pathway. Studies have shown good efficacy and safety with 4-n-butylresorcinol in patients with melasma.

Huhet al. conducted a randomized controlled split-face trial in 23 patients with melasma to evaluate the efficacy and safety of liposome-encapsulated 4-n-butylresorcinol 0.1% cream. They found a statistically significant reduction (P < 0.043)="" in="" the="" melanin="" index="" on="" the="" treatment="">

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