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Egyptian Dermatology Online Journal
Vol. 1 No 2:8, December 2005
Why vitiligo in diabetes?
O. A. Olasode, MBBCH, FWACP
Egyptian Dermatology Online Journal 1 (2): 8
Obafemi Awolowo University, College Of Health Sciences, Ile Ife,
Osun State, Nigeria.
[email protected]
Submitted and accepted for publication in September, 2005
Introduction
Diabetes Mellitus is a group of metabolic diseases that share
the phenotype of hyperglycemia. The metabolic deregulations
associated with diabetes causes secondary pathophysiological
changes in multiple organ systems including the skin. Diabetes
mellitus is associated with many skin diseases one of which is
vitiligo.
Vitiligo is an acquired idiopathic disorder of melanogenesis
characterized by depigmented macules in an otherwise normal
skin. Why does vitiligo develop in diabetes? What is responsible
for the depigmentation of vitiligo in diabetes? Sezary and Dupuy
[1] were the first to mention the association between diabetes and
vitiligo and they attributed the skin discoloration to some
pancreatic influence. Since that time, many cases of diabetes with
vitiligo has been documented [2, 3].
The incidence of diabetes mellitus in vitiligo patients ranges
between 1-7% in literature and vitiligo may precede the onset of
diabetes mellitus [4]. Dawber [5] suggested that diabetes mellitus
should be excluded in all cases of late onset vitiligo. Among 457
diabetic subjects attending an outpatient clinic, 9% had vitiligo
lesions [6]. In another series in Karachi, 10% of 100 patients with
diabetes mellitus had vitiligo compared with incidence of 1% in
general population [7]. Vitiligo is a consistent finding in literature
concerning skin complications of diabetes. The possible
etiopathogenesis of this relationship need consideration.
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Vol. 1 No 2:8, December 2005
The Autoimmune Connection:
Both diabetes and vitiligo share a common theory of
autoimmunity. The evidence to support that insulin dependent
diabetes is a slow autoimmune disease include HLA-linked genetic
predisposition, association with other autoimmune disorders,
circulating islet cell and insulin autoantibodies, mononuclear cell
infiltration of pancreatic cells and recurrence in pancreatic grafts
[8]. Anti-islet cells have been documented in insulin dependent
diabetes.
Whittingham et al [9] noted an increased level of
autoantibodies in four hundred diabetics particularly those with
insulin dependent diabetes. Pathologically, particularly in Type 1A
Diabetes, the pancreas is infiltrated with lymphocytes causing
inflammation followed by Islet cell atrophy. There are activated T
cells, release of lymphokines, tumor necrosis factor, Interferon and
Interleukin [10]. Vitiligo also has been found to be associated with
diseases believed to be autoimmune such as Grave’s disease,
Hashimoto thyroiditis, pernicious anemia, alopecia areata,
Addison’s disease and diabetes mellitus [11].
Immunosuppressive therapy has been found to be effective in
the treatment of vitiligo. Antimelanocyte antibody has been
isolated in vitiligo [1]. A primary disturbance in immunological
mechanisms is what results in melanocyte dysfunction. This results
in inhibition of melanin production or melanin cytotoxicity. An
alternative mechanism is that some injuries to melanocytes result in
the release of antigenic substance so that antibody formation occurs
and melanogenesis is inhibited [1].
The occurrence of vitiligo in diabetes may be as a result of a
basic autoimmune disturbance in the same patient affecting two
organ systems. Longstanding Diabetes Mellitus may cause an
injury to melanocytes resulting in the release of an antigenic
substance, antimelanocyte antibody formation, inhibition of
melanogenesis and occurrence of vitiligo.
There is considerable evidence that depigmentation may be an
important cutaneous marker for immunological based diseases. The
depigmentation of vitiligo is seen in halo naevus, malignant
melanoma and Vogt-Koyanagi-Harada syndrome [1]. In patients
with halo naevus, vitiligo surrounds a melanocytic naevus, which is
a localized developmental abnormality of the skin with increased
number of melanocytes. Halo naevus is considered as an immune
process and vitiligo can occur at remote sites.
Vitiligo occurs in malignant melanoma following stimulation
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of the immune system arising from damaged and aberrant
melanocytes. This vitiligo may occur at sites distant to the primary
lesion and in regressing lesions melanomas. Clinical
depigmentation occurs in Vogt-Koyanagi-Harada syndrome in
which hypersensitivity to uveal pigments and disturbances of cell
mediated immunity is found [1].
Genetic Considerations
Diabetes mellitus and vitiligo share a common risk factor of
familial predisposition. Diabetes is often present in close relatives
of patients with Vitiligo [12]. Both diabetes and vitiligo are
associated with HLADR3 and HLADR4 [13]. No race is spared in
vitiligo and diabetes. Vitiligo has been observed in monozygotic
twins although the extent, age of onset, and course may be similar
or dissimilar in to the other twin [14].
Inheritance pattern is thought to be autosomal dominant with
variable penetrance. In 30% of vitiligo patients there is history of
vitiligo in another family member [1]. The occurrence of Type1A
Diabetes in identical twins ranges between 30-70% [10]. Maturity
onset diabetes of the young (MODY) is of autosomal dominant
inheritance [10].
Mutations in insulin receptor cause a group of rare disorders
characterized by severe insulin resistance. The genetic
contributions to diabetes mellitus involve multiple genes and
development of the disease requires inheritance of sufficient
complements of genes to confer susceptibility. The major
susceptibility gene is located on HLA region on chromosome 6.
This region contains genes that encode the classic 11 MHC
molecules that present antigens to helper T cell that are involved in
initiating an immune response [10]. The genetic predisposition can
therefore be linked with autoimmunity. It is possible that the same
patient may have a genetic predisposition to both vitiligo and
diabetes as opposed to a causal relationship.
Cell Destruction Theory
Lerner proposed the self-destruction theory of vitiligo [15].
He said that melanocytes are destroyed by the very factors that are
required for melanogenesis. He proposed that a melanin precursor
might have a toxic lethal effect when the naturally occurring
protective mechanisms are lost. There is usually a selective
destruction of melanocytes in vitiligo. The two known mechanisms
for the destruction of cells are necrosis and apoptosis. Some
workers reviewed available data to find out which of the two
mechanisms was operative in vitiligo. The histological data and
some laboratory data suggested apoptosis rather than necrosis as
the mechanism for the removal of melanocytes [16]. Apoptosis can
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be induced by a variety of factors including immune cytokines.
Moretti et al [17] found that a significant amount of epidermal
cytokines exists in vitiligo skin compared with perilesional, nonlesional and healthy skin suggesting that cytokine production of
epidermal microenvironment may be involved. Confirmation of
apoptosis as a mechanism in causation of vitiligo in diabetes can
serve as a basis for devising medication to stop the disorder. The
study of apoptosis, mechanism of its induction, and the ways to
block apoptosis is one possible way to find the cause of
depigmentation in diabetes mellitus.
Diabetic Neuropathy and Neurologic Theory
Nervous system affectation in diabetes called diabetic
neuropathy affects 50% of individuals with longstanding diabetes.
It manifests as polyneuropathy, mononeuropathy, autonomic
neuropathy or a polyradiculopathy. Affectations of multiple
isolated nerves result in mononeuritis multiplex [10].
Histopathological findings in diabetic neuropathy reveal axonal
shrinkage, fragmentation, and degeneration of both myelinated and
unmyelinated nerves. There are also abnormalities of intraneural
capillaries, thickening of basement membrane and micro thrombi
[10].
Can the neuronal damage in diabetic neuropathy account for
development of vitiligo in diabetes? Dermatomal vitiligo has been
associated with dysfunction of sympathetic nerves in affected skin
areas [18]. Yokota [18] noted degenerative changes in the terminal
portions of peripheral nerves in vitiliginous areas by using
histochemical studies and Mori [19] in 1964 using the light
microscope.
Numerous clinical observations have been reported in which
vitiligo patients became white in cutaneous areas corresponding to
areas of neurological damage [4]. Leukoderma occurring in a
leprous macule would favor neurogenic hypothesis of leukoderma
since the leprosy bacillus primarily affects the nerves. The fact
remains however that vitiligo lesions have no sensory loss.
Spontaneous repigmentation has been documented in vitiligo
lesions of diabetic neuropathy and loss of Merkel cells have been
seen in early vitiligo lesions [20].
General Mechanisms of Diabetic Complications
The primary disturbance in diabetes is chronic hyperglycemia.
There are three major theories on how hyperglycemia leads to
chronic complications in organ systems.
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Glycosylation of cellular proteins
Increased intracellular glucose leads to formation of advanced
glycosylation end products via non-enzymatic glycosylation of
cellular proteins. This causes atherosclerosis, glomerular
dysfunction, reduced nitric oxide synthesis, endothelial dysfunction
and alteration of cellular matrix.
The Sorbitol pathway
Increased glucose metabolism through sorbitol pathway,
which affects various aspects of cellular physiology causing,
decreased myoinositol and altered redox potential and cellular
dysfunction.
Increased Diacylglycerol
Increased formation of diacylglycerol leads to activation of
certain isoforms of protein kinase C (PKC) that alters gene
transcription for fibronectin, collagen, contractile proteins and
extra cellular matrix proteins.
Conclusion
The occurrence of depigmentation of vitiligo is certain but the
etiopathogenesis remains an enigma. Vitiligo and diabetes may
have a causal relationship and both are associated with
autoimmunity.
Familial-hereditary tendencies occur in both diseases. There is
neuropathic complications in diabetes and in vitiligo
dermatodermal variety occur with evidence of degenerated nerve
endings. Multiple pathogenetic mechanisms may be involved.
Vascular and non-vascular pathogenetic mechanisms play a role in
diabetic complications. The products of oxidative stress, free
radical generation and release of various growth factors may be
cytotoxic affecting melanogenesis.
References
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