SUNG BIN I M, M D Department of Dermatology, Ajou University School of Medicine, 5 Wonchon-don'y, Paldal-ku, Suwon, 442-722, Korea. SC H A L L R E U T E R, dr. of Clinical and Experimental Dermatology, Department of Biomedical Sciences, University of Bradford, United Kingdom and Institute of Plimentary Disorders in association with E.M.
Acknowledgements
PART 1
The definition of vitiligo
We think that this type of hair depigmentation is not the same disorder as vitiligo vulgaris and the two forms of depigmentation should be distinguished. The other type of full head white hair is uncommon but is associated with vitiligo.
The Loss of Melanocytes from the Epidermis: the Mechanism for
Skin color is determined to a large extent by the amount and type of melanin within the epidermis (Nordlund et al. 1998). Absence of melanocytes from the epidermis at birth is called piebaldism, a term meaning white streaked.
Histological studies
Melanocyte cultures
Response to therapy
History and Cultural Aspects of Vitiligo
Historical references about vitiligo
Vitiligo in writings from dates before Christ (BC)
Biblical references to vitiligo
Histo y and The origin of the word vitiligo
Vitiligo in the 19th Century
Genetics and Prevalence of Vitiligo Vulgaris
One of the major problems with these early studies of the genetics of vitiligo was that they did not account for the variable age at onset of vitiligo. The incidence and mean age at onset of vitiligo varies considerably between different geographic regions and ethnic groups.
CHAPTER 4 References
PART 2
Histology of Vitiliginous Skin
However, the current consensus on the histological presentation of vitiligo is that the amelanotic lesion contains no melanocytes, that the border shows both melanocytic and keratinocyte damage, plus occasional mononuclear leucocyte infiltrates. In this chapter, a compilation of the literature on the histological profile of vitiligo is presented.
The histology of the amelanotic vitiligo lesion
Melanocytes in the stratum basalum of the epidermis appear as round cells with relatively clear cytoplasm (arrows) in the African American individual (a) and the OCAl patient (c), but are absent in the lesional skin of the patient with vitiligo (b ) . Birbeck et al. 1961) initially reported the presence of DOPA-negative, gold chloride-positive dendritic cells in the basal layer of vitiliginous epidermis.
The histology of the border between the lesion and normal skin
In most reports, in the non-inflammatory form of vitiligo, a clear influx of lymphocytes into the skin of the amelanotic lesion and, importantly, at the border was generally not observed. The presence of B cells in the border of vitiligo lesions has not yet been confirmed by immunocytochemistry.
The histology of the normally pigmented skin
It has also been shown that melanocytes in the pigmented skin of patients with vitiligo can exhibit an expansion of the rough endoplasmic reticulum (RER) that is not present in control skin (Fig. 5.5; Boissy et al. 1991). Therefore, the pigmented skin of patients with vitiligo may not be as healthy and unaffected as previously thought.
Summary
Clinical Features of Generalized Vitiligo
Introduction
Age of onset
It seems likely that women seek medical attention for treatment of vitiligo sooner after onset than men. That women have an increased concern for the appearance of their skin contributes to an early sensitization of the condition and earlier presentation to a dermatologist for treatment.
Precipitating factors
Characteristics of lesions
Distribution of vitiligo
Involvement of the ventral wrist may be associated with vitiligo of the palms (Figs. 6.1 & 6.2). In addition to the mucous membranes of the mouth, vitiligo often occurs on the genitalia, areola, and nipples (Song et al. 1994).
Involvement of body and scalp hair
The interfollicular epidermis of the scalp is frequently overlooked as a site of depigmentation, although the melanocytes in the hair follicles are spared. The involvement of the skin of the scalp is usually noticeable in those with dark skin.
Clinical classification of vitiligo
The incidence of each type of vitiligo according to this classification varies from study to study. The central border of this type of vitiligo does not cross the midline (Barona et al.
Course of vitiligo
However, when the hands were the initial site, vitiligo most often progressed to the face. The pattern of progression of non-segmental vitiligo was usually close to the initial site, regardless of location.
Factors affecting progression of vitiligo
Koebner's phenomenon refers to the development of vitiligo or other skin conditions after a physical injury, such as a cut, burn or abrasion, and is present in at least one third of vitiligo patients (Moscher 1993). Significant progression of vitiligo in patients with mucosal involvement suggests that it is a poor prognostic factor.
Clinical characteristics of bilateral vitiligo
When focal vitiligo first appears as a single lesion, it may not be easy to determine the type of vitiligo. It is not known what percentage of focal vitiligo progresses to other types of vitiligo.
Conclusion
Clinical Features of Segmental Vitiligo
Koga (1977) divided vitiligo into two variants, type A, which is characterized as bilateral, non-segmental vitiligo; and type B, segmental form. Segmental vitiligo usually appears early in life and spreads rapidly within the affected area, which is limited to one segment of the sheath.
Incidence
The course of the segmental type may stop and the depigmented spots may remain unchanged for the life of the patient. This feature is very strikingly different from the chronic progressive course of bilateral, nonsegmental vitiligo (Koga & Tango 1988; Hann & Lee 1996).
Site of involvement
Distribution of lesions
The lesion starts from the left side of the face and extends along the right side of the face, across the midline (Fig. 7.3). In type 4, the lesion originates from the right side of the forehead and spreads to the eyeball, nose and cheek areas without crossing the midline (Fig. 7.6).
Progression of lesions
The right side was affected in 57 out of 125 right-handers, while in the left-handers four had left-sided involvement and four right-handers. A white spot on the nipple or areola that appears as an initial lesion can be assumed to be an early sign of segmental vitiligo (Figure 7.8).
Family history
Koebner’s phenomenon
Associated disease
Koga and Tango (1988) claimed that autoimmune disease associated with vitiligo was more significant in non-segmental vitiligo than in segmental vitiligo and that this difference could be due to different pathogenic mechanisms. In the study by Hann and Lee (19961), an association with thyroid disease, diabetes mellitus, pernicious anemia and halo nevus was observed in 3.4% of patients with segmental vitiligo (Koga & Tango 1988; Park et al. 1988).
Bilateral segmental vitiligo
The lesions on the right side are located on the shoulder and arm, while the lesions on the left side are located in the lower chest and upper abdomen, which do not cross the midline. Treatment with PUVA and steroid therapy can induce repigmentation or arrest the progression of vitiligo lesions in bilateral segmental vitiligo.
Treatment
Childhood Vitiligo: Clinical Spectrum and Therapeutic Approaches
Their patients had an increased frequency of segmental vitiligo and strong family history of autoimmune disease compared to adults. Tango 1988; Hann & Lee 1996) also reported an increased frequency of segmental vitiligo in pediatric patients with vitiligo.
Spectrum of disease
Tango 19881, the frequency of segmental vitiligo in our study was significantly increased in children (Fig. 8.2). The frequency of associated diseases in children with vitiligo is significantly less than observed in the adult vitiligo population (Table 8.2).
Therapeutic approaches
Special Features of Vitiligo
Trichrome vitiligo
The isomorphic response
At least two studies conclude that the IKP is significantly more common in patients with progressive vitiligo (Schallreuter et al. There appears to be a minimal threshold of injury necessary for the IKP to occur (Gopinathan 1965).
Vitiligo with raised borders
The induction of the IKP was observed more often in the skin adjacent to the lesions than in distant locations, indicating a difference in reactivity of unaffected skin to epidermal trauma in the same patient (Gopinathan 1965). The IKP may be a good explanation for the onset or spread of vitiligo due to severe sunburn.
Blue vitiligo
In a few cases of coexistence of vitiligo and lichen planus (LP), the typical polygonal papules of LP were arranged on the pigmented border of some vitiligo macules, but did not give the characteristic appearance of a red, linear border marking the junction. affected and unaffected skin (Figure 9.5) (Baran et al. 1997).
Vitiligo ponctuC
Depigmentation of Hair and Mucous Membranes
Oral vitiligo
Depigmentation of hair
Ocular and Otic Findings in Vitiligo
1 the pigment epithelial layers of the retina, ciliary body and iris, and 2 the melanocytes of the uvea. In patients with vitiligo, both types of pigmented cells of the eye, as well as the melanocytes in periocular cutaneous tissues, may be affected, presumably by the same pathophysiological mechanism that affects the skin.
Vitiligo and ocular disease
A late consequence of VKH is the depigmentation and scarring of the ocular fundus, which occurs in the convalescent phase (Fig. 11.2). Non-inflammatory depigmented lesions of the fundus are observed in 18-31% of patients with non-VKH vitiligo (Albert et al.
Vitiligo and otic disease
The Association of Vitiligo with Disorders of Other Organ Systems
The etiology of vitiligo remains a mystery, but the most popular theory is based on an autoimmune mechanism. Numerous reports have been published by investigators around the world to document an association of vitiligo with the immune system (reviewed in Nordlund et al. 1998).
Vitiligo and endocrine dysfunction
This idea that vitiligo and melanocyte destruction is caused by an autoimmune process appears to have been first proposed in the 1960s (Cunliffe et al. 1968) when the immune system was under intense study. The first report of an association of vitiligo and thyroid dysfunction appears to have been published in 1968 (Cunliffe et al. 1968).
Vitiligo and haematological dysfunction
The Psychological Effects of Vitiligo
The tendency of many doctors to trivialize vitiligo and its consequences was one of the most difficult problems faced by patients (Porter et al. 1978). 1988) Older adults' response to impaired appearance: The effect of Porter, J. 1991) Racial variation in response to physical stigma: a study of.
Differential Diagnosis of Vitiligo Vulgaris
PRANAV 8. SHETH
However, the cluster of cutaneous and extracutaneous findings of TSC, the random nature of ash-leaf macules, and the consistency of the lesions help establish the diagnosis. The characteristic linear and rounded pattern of lesions and the distribution of pigmented lesions in HI allow this disorder to be easily distinguished from vitiligo.
Inflammatoryheoplastic disorders
Distribution is common on the face, neck, shoulders and extensor surface of the arms (Fig. 14.8). Hypomelanotic macules distributed on the trunk and limbs, the largest on the legs, have been described in patients with sarcoidosis (Fig. 14.9).
Infectious disorders
The hallmark of the tertiary or late stage is depigmented lesions on the bony prominences, wrists, elbows, and ankles. These symmetrical, depigmented lesions develop 3 months to 10 years after the appearance of secondary lesions (called pintids) which are psoriasiform papules and plaques (Koff & Rosen 1993).
Idiopathic disorders
Post-inflammatory hypopigmentation and depigmentation can have a variety of presentations based on the preceding inflammatory response or insult. Repigmentation is based on a host of factors, including the age of the patient, the type of insult or injury, the location on the skin and the presence of hair follicles.
Differential diagnosis of segmental vitiligo
PART 3
PATHOGENESIS OF
VITILIGO: THEORIES FOR DE PIG MENTATION
The Intrinsic (Genetic) Theory for the Cause of Vitiligo
As stated in this comprehensive monograph, the etiology of vitiligo is not clearly understood. Therefore, regardless of whether a single or multiple initiating events are responsible for the development of vitiligo, it is likely that an underlying genetic/intrinsic factor predisposes the melanocyte of an individual to be more sensitive to these various causative factors.
Inheritable component
Currently, several causative factors are involved in the depigmentary processes of vitiligo, including cytological, environmental, immunological, and neurological destruction of the melanocytes. In a recent epidemiological study of 15,685 individuals from 298 families, researchers found a sevenfold increase in vitiligo in primary relatives of individuals with vitiligo (Nath et al. 1994).
Inherent defects
Theories on the Pathogenesis of Depigmentation: Immune Hypothesis
Loss of pigment under these conditions may occur in otherwise normal skin, around or within a benign or malignant pigmented lesion, or at a site distal to the pigmented lesion. These different forms of leucoderma are probably the result of different pathophysiological mechanisms, as they involve the destruction of different types of pigment cells, i.e.
Pathogenesis of leukoderma in vitiligo
They also have the ability to kill melanocytes in vim when administered passively to nude mice grafted with human skin (Gilhar et al. 1995). Although antibodies against tyrosinase were initially reported in 61% of 26 patients with vitiligo (Song et al. 19941), subsequent studies have not confirmed this association.
Role of immune mechanisms in the pathogenesis of vitiligo
- Autocytotoxic Hypothesis for the Destruction of Melanocytes as the
They likely involve complement-dependent and antibody-dependent cellular cytotoxicity (ADCC), as anti-vitiligo antibodies can kill melanocytes in vitro by both mechanisms. 1993) Coexistence and relationship of antikeratinocytes. and antimelanocyte antibodies in patients with nonsegmental vitiligo. 1996) Anti-tyrosinase antibodies in vitiligo.
The autocytotoxic theory for the destruction of melanocytes
Neural Pathogenesis
The neural theory is supported by clinical, physiological, microscopic, ultrastructural, immunohistochemical, and biochemical findings.
Clinical evidence for the neural hypothesis
Vitiligo has developed in the area supplied by nerves damaged after brachial plexus injury, suggesting that the 'sympathetic repercussion' ended in depigmentation (Costea 1961). Spontaneous repigmentation of extensive vitiligo has been described in the areas anesthetized by diabetic neuropathy (Lerner 1972).
Physiological evidence for the neural hypothesis
One patient with transverse myelitis, paralyzed from the waist down, had vitiligo only in the upper part of the body and preservation of pigmentation in the areas below the level of cord damage (Lerner et al. 1966). A numerical decrease of active melanocytes in the inner ear, leading to an obstruction of the ion exchange between the endolymph and perilymph, has been proposed to explain the abnormalities of the auditory brainstem response to vitiligo (Nikiforidis et al. 1993).
Microscopic and ultrastructural findings
Sudomotor dysfunction has also recently been shown to be an abnormal sympathetic response (Merello et al. 1993). The grafted skin acquires the properties of the area where it is transplanted only after the local innervation has taken place (Haxthausen 1947; Spencer & Tolmach 1952; Eriksson et al. 1968).
Immunohistochemical findings
Biochemical evidence for the neural hypothesis
Biochemical Theory of Vitiligo: a Role of Pteridines in Pigmentation
Clinical signs of vitiligo are white patches along with normally pigmented skin in the same individual (Fitzpatrick et al. 1979). We attribute this fluorescence to the accumulation of two different oxidized pteridines, 6-biopterin with bluish fluorescence and 7-biopterin, its isomer, with yellow/green fluorescence (Schallreuter et al. 199413, c).
What are these pteridines and what is their physiological role/function?
A significant decrease in the number of functioning epidermal melanocytes or their complete absence in the white skin of affected individuals has been described (Gokhale &. The cofactor serves for phenylalanine hydroxylase in the presence of oxygen (0,) to convert the essential amino acid L-phenylalanine to L-.
Pteridines in the human epidermis
Only very recently has the presence of 4a-OH-tetrahydrobiopterin dehydratase in epidermal keratinocytes been confirmed by Lei et al. The presence of specific mRNA for GFRP has only recently been identified for the first time in melanocytes and keratinocytes (Schallreuter et al. 1998).
The redox status of the pteridines controls 6BH4-dependent enzyme activities where the oxidized pterins are inactive (Schallreuter-Wood & Wood 1995; Wood et al. 1995). However, it has been demonstrated that 2 x l@7 M 6-biopterin is cytotoxic to human melanocytes under in vitro conditions (Schallreuter et al. 1994a).
Impaired L-phenylalanine turnover in vitiligo
PART 4
The Melanocyte Reservoir and its Necessity
There are no identifiable melanocytes in the epidermis and hair follicle matrices of vitiligo lesions. The clinical observation that early repigmentation usually occurs at the mouth of the hair follicle indicates that a melanocyte reservoir may reside in the hair follicle.
Melanocyte reservoir of hair follicle
Inactive melanocytes divide, proliferate, and migrate upward along the surface of the hair follicle to the nearby epidermis, where they continue to move radially and downward to the hair matrix. Further characterization of these melanocytes by immunohistochemistry and immunoelectron microscopy revealed that the majority of inactive melanocytes in 0% were found in the middle to upper part of the hair follicles and were easily identified using MoAb NKI/beteb and A4Fl1, which recognizes premelanosome- related antigens (Horikawa et al. 1996; Narisawa et al. 1997).
Proliferation of follicular melanocytes
On the other hand, focal contact proteins, transmembrane proteins that connect the extracellular matrix to the actin cytoskeleton of cells and play a key role in controlling melanocyte migration (Scott et al. 1995), can also be modified to improve melanocyte motility. . 1962) Activation of amelanotic melanocytes in the outer root sheath of the hair follicle after ultraviolet exposure.
Selection of patients
It is not known whether this is an effect of the therapy or the natural course of the vitiligo. PUVA therapy for vitiligo is not a quick treatment and therefore it is important to initially determine to what extent the disease concerns the patient and how easily a long and uncomfortable therapy will fit into their lifestyle.
Treatment protocols
Patients should avoid exposure to sunlight from the time of taking psoralen until sunset, and eye protection is essential for the same period of time. Topical PUVA therapy is intuitively preferred when treating limited CHAPTER 21 disease as it avoids systemic exposure to the drug.
Response to treatment
Steroid Treatment for Vitiligo
It can have side effects such as fatigue, headache, dizziness, stomach discomfort and rarely hepatitis (Hann et al. 1992). In patients who have failed or are not suitable for PUVA, other types of therapy should be used.
Topical steroids
On the face, patches of the eyelid and lateral sides of the orbit are satisfactorily repigmented by topical steroids. From Moon et al.S study (1995), segmental vitiligo that occurs on the face or is of short duration responds well to topical steroids (Fig. 22.1).
Intralesional corticosteroids
If there is no repigmentation of hair or skin with triamcinolone acetonide injections, topical PUVA can be started after shaving.
Systemic steroids
Seventeen patients experienced one or more of the following side effects: weight gain, bad taste, headache, transient mild weakness for 2 days, acne, mild facial bags, perioral dermatitis, herpes zoster, glaucoma, or amenorrhea. 1995) also studied the effectiveness of oral mini-pulse therapy for vitiligo. Thirty-five patients had no side effects with this treatment regimen, while 46 patients complained of one or more of the following: facial edema was the most common side effect and was noted in 17 (21%) of 81 patients; weight gain and acne-like eruption occurred in eight (9.9%) patients, respectively.
Other steroids
Pseudocatalase in the Treatment of Vitiligo
Increased sensitivity to hydrogen peroxide (H,O,) has been documented in normal human melanocytes under in vitro conditions (Yohn et al. 1991). We were able to demonstrate oxidative stress/vacuolation in freshly established cell cultures of melanocytes and keratinocytes from affected and unaffected skin of these patients (Schallreuter et al. 1999).
Low catalase levels in vitiligo
Nowadays there is increasing evidence for increased oxidative stress throughout the epidermis of these patients. Several reports have shown previous peroxidative damage in melanocytes and in keratinocytes, where vacuolar degeneration and granular deposits have been described in both involved/pigmented and uninvolved/normally pigmented epidermis (Moellman et al. 1982; Bhawan & Bhutani 1983; Boissy et al. 1991).
