Download Acanthosis Nigricans - Abdel Hamid Derm Atlas

Association of acanthosis nigricans
and skin tags with insulin resistance
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Acanthosis nigricasns (AN) lesions and skin tags should never be ignored, since they
bring information about internal diseases and, therefore, can offer some guidance as
to how to proceed about these diseases, preventing a series of future morbidities
such as diabetes and atherosclerotic diseases.
Although often disregarded by patients, since they are asymptomatic lesions, these
dermatoses are of great importance and cannot go unnoticed in the clinical
examination, since they can serve as indicators of the need to measure laboratory
data that may lead to a diagnosis of insulin resistance.
Insulin resistance (IR), like smoking, alcohol abuse and violence in traffic, represent
one of the most important modifiable factors for promoting health and reducing
mortality in general.
Insulin resistance has been associated with AN and acrochordons (AC), and it is
known that early diagnosis and early treatment are of paramount importance to
prevent a series of future manifestations. Reduction of insulin action may be
accompanied by a group of metabolic disorders such as @ hypertension, @
hypertriglyceridemia, @ reduced HDL/cholesterol levels, @ carbohydrate intolerance,
@ central obesity, @ increased plasminogen activator inhibitor-1 concentrations
(fibrinolytic disorders), @ hyperuricemia and @ atherosclerotic cardiovascular
disease. This set of changes is known as insulin resistance syndrome or metabolic
syndrome. Therefore, AN becomes an easy signal for tracking insulin resistance and
non-insulin-dependent diabetes mellitus (DM), with implications regarding changes in
lifestyle and adoption of early treatment.
Acanthosis Nigricans
Acanthosis Nigricans
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Acanthosis nigricans (AN) is characterized by symmetrical, hyperpigmented, velvety lesions, which can occur
anywhere in the body, but especially in the armpits, groin, neck, antecubital and popliteal fossae and umbilical
region . Less often it affects eyelids, palms, soles of the feet, nipples and phalanges . In rare cases, it can affect
the mucosa of the mouth, respiratory mucosa and genital region. These lesions may be skin-colored or brownish
and may vary between 1 mm and 1 cm.
Acanthosis nigricans has been divided into 7 types (details of which is seen in the following slide)
The features of acanthosis nigricans:
@ Thickened brown velvety textured patches of skin that may occur in any location but most commonly appear in
the folds of the skin in the armpit, groin and back of the neck.
@ Papillomatosis (multiple finger-like growths) is common on cutaneous and mucosal surfaces.
@ Skin tags often found in and around affected areas.
@ Pruritus (itching) may be present, particularly in acanthosis nigricans associated with malignancy
(paraneoplastic pruritus).
@ AN lesions may also appear on the mucous membranes of the oral cavity, nasal and laryngeal mucosa and
oesophagus.
@ Lesions involving the mucosa, palms and soles tends to be more extensive and more severe in malignant AN.
@ Patients with malignant AN tend to be middle-aged, not obese and lesions develop abruptly.
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Endocrinopathies are the major causes of AN, and obesity is the most common disorder, often associated with
hyperinsulinism, diabetes mellitus and insulin resistance. Other endocrine disorders associated with AN are
described, such as Cushing's syndrome, polycystic ovaries, thyroid diseases, hirsutism, Addison's disease,
acromegaly, among others, some of which occur with insulin resistance.
The mechanism through which insulin resistance causes acanthosis is complex. The significant presence of IR
produces compensatory hyperinsulinemia. Increased serum insulin levels interact with insulin-like growth factor
receptors (IGF-1) triggering proliferation of keratinocytes and fibroblasts . AN is caused by factors that stimulate
epidermal keratinocyte and dermal fibroblast proliferation. In forms associated with malignancy, substances
secreted by the tumor are thought to act as stimulating factors. It is postulated that TGF-alpha, which is produced
by the tumor and is similar to EGF,
Acanthosis nigricans has been divided into 7 types.
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@Obesity-associated acanthosis nigricans
Most common type of AN
May occur at any age but more common in adulthood
Obesity often caused by insulin resistance
@ Syndromic acanthosis nigricans
Defined as AN that is associated with a syndrome, e.g. hyperinsulinaemia, Cushing's syndrome, polycystic ovary
syndrome,total lipodystrophy
@ Benign acanthosis nigricans
Also referred to as acral acanthotic anomaly
Thick velvety lesion most prominent over the upper surface of hands and feet in patients who are in otherwise
good health
Most common in dark-skinned people, especially those of African American descent
@ Drug-induced acanthosis nigricans
Uncommon, but AN may be induced by several medications, including nicotinic acid, insulin, systemic
corticosteroids and hormone treatments
@ Hereditary benign acanthosis nigricans
AN inherited as an autosomal dominant trait
Lesions may manifest at any age, infancy, childhood or adulthood
@ Malignant acanthosis nigricans
AN associated with internal malignancy
Most common underlying cancer is tumour of the gut (90%) especially stomach or liver cancer
In 25-50% of cases, lesions are present in the mouth on the tongue and lips
@ Mixed-type acanthosis nigricans
Patients with one type of AN whom also develop new lesions of a different cause, e.g. overweight patient with
obesity-associated AN who then develops malignant AN
Acanthosis nigricans
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Symptoms:
@Acanthosis nigricans usually appears slowly and doesn't cause any symptoms other than skin changes
@ Eventually, dark, velvety skin with very visible markings and creases appears in the armpits, groin and neck
folds, and over the joints of the fingers and toes
@ Less commonly, the lips, palms, soles of the feet, or other areas may be affected
Do's and Dont's of Acanthosis Nigricans
Do's:
1.
Differentiate between benign and malignant with the help of a dermatologist
2.
Reduce body weight
3.
Strict control of diabetes if already diagnosed
4.
Regular aerobic exercises
5.
Full investigations including tumor markers, hormonal assay, ultra sound scan, MRI etc
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Regular medical check up, semi annual
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Report any sudden changes in morphology , i.e, color, margins, spread, texture etc.
Don'ts
1.
Scrub too much, as frequent rubbing will only increase skin thickening and pigmentation
2.
Use strong abrasives: tend to irritate the skin more.
Differential diagnosis
@ Epidermal nevus
@ Seborrheic keratosis
@ Oral lesions may resemble Condyloma accuminta
Acanthosis nigricans : Differences between benign &
malignant AN.
Causes Acanthosis Nigricans
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What Causes Acanthosis Nigricans?
Acanthosis nigricans skin patches occur when epidermal skin cells begin to reproduce rapidly. This abnormal skin cell growth is most
commonly triggered by high levels of insulin in the blood. In rare cases, the increase in skin cells may be caused by medications, cancer,
or other medical conditions.
Too Much Insulin
The most frequent trigger for acanthosis nigricans is too much insulin in your bloodstream.
When you eat, your body converts carbohydrates into sugar molecules such as glucose. Some of this glucose is used for energy in your
cells while the rest is stored. The hormone insulin must allow glucose to enter cells so that the cells can use glucose for energy.
Overweight people tend to develop resistance to insulin over time. Although the pancreas is making insulin, the body can’t use it properly.
This creates a buildup of glucose in the bloodstream, which can result in high levels of both blood glucose and insulin in your
bloodstream.
Excess insulin causes normal skin cells to reproduce at a rapid rate. For those with dark skin, these new cells have more melanin. This
increase in melanin produces a patch of skin that’s darker than the skin surrounding it. Thus, the presence of acanthosis nigricans is a
strong predictor of future diabetes. If too much insulin is indeed the cause, it’s relatively easy to correct with proper diet, exercise, and
blood sugar control.
Medications
Acanthosis nigricans can also be triggered by certain medications such as birth control pills, human growth hormones, thyroid
medications, and even some bodybuilding supplements. All of these medications can cause changes in insulin levels. Medications used to
ease the side effects of chemotherapy have also been linked to acanthosis nigricans. In most cases, the condition clears up when the
medications are discontinued.
Other Potential Causes
In rare cases, acanthosis nigricans can be caused by:
- stomach cancer, or gastric adenocarcinoma
- adrenal gland disorders, such as Addison’s disease
- disorders of the pituitary gland
- low levels of thyroid hormones
- high doses of niacin
How Is Acanthosis Nigricans Diagnosed?
Acanthosis nigricans is easy to recognize by sight. Your doctor may want to check for diabetes or insulin resistance as the cause. These
tests may include blood glucose tests or fasting insulin tests. Your doctor may also review your medications to see if they’re a contributing
factor.
It’s important to tell your doctor about any dietary supplements, vitamins, or bodybuilding supplements you may be taking in addition to
your prescription medications.
Syndromes and hormone problems in acanthosis nigricans
• Syndromes and hormone problems:
• Acanthosis nigricans is sometimes associated with an underlying
syndrome or hormone problem, such as:
• @ polycystic ovary syndrome – a condition that affects how a
woman's ovaries work, which can cause excessive body hair,
irregular periods, infertility, acne and weight gain
• @ Cushing's syndrome – symptoms such as weight gain, bruising
and stretch marks caused by very high levels of the hormone
cortisol in the body
• @ acromegaly – where the body produces too much growth
hormone, leading to the excess growth of body tissues over time
• @ underactive thyroid (hypothyroidism) – where your thyroid gland
does not produce enough hormones, causing symptoms such as
tiredness and weight gain
• This type of acanthosis nigricans is known as syndromic acanthosis
nigricans
Polycystic ovary syndrome
Acanthosis Nigricans
Acanthosis
Nigricans
Acanthosis Nigricans
Acanthosis nigricans
Acanthosis nigricans and "tripe
palm" as paraneoplastic
manifestations of metastatic
tumor
Acanthosis nigricans and "tripe palm" as paraneoplastic manifestations of
metastatic tumor
An. Bras. Dermatol. 87 .3 Rio de Janeiro 2012
Acanthosis Nigricans
Oral Acanthosis Nigricans
N Engl J Med 2007; 357:10, 2007
Oral malignant acanthosis nigricans associated with endometrial
adenocarcinoma
International Journal of Oral Science (2014) 6, 247
Oral malignant acanthosis nigricans associated with endometrial
adenocarcinoma
International Journal of Oral Science (2014) 6, 247
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Histological slide of lips showing hyperkeratosis, acanthosis, increased dermal
pigmentation and papillomatous hyperplasia of the epidermis.
Histology of Acanthosis nigricans
Histology of
Acanthosis nigricans
• Orthokeratotic
hyperkeratosis
(not actually
acanthosis) and
papillomatosis of
stratum
spinosum
• Hyperpigmentati
on of basal cell
layer, but no
melanocytic
hyperplasia
• Usually no
dermal
inflammation
Acanthosis nigricans
Histology of Acanthosis nigricans
Dermatology Online Journal 14 (9): 2
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Histopathology :
reveals a thickened
stratum corneum with
minimal involvement of the
dermis except for
thickened and elongated
dermal projections.
Despite the term
"acanthosis," the actual
amount of acanthosis, or
thickening of the stratum
spinosum, is variable and
typically mild . The dark
color of AN is likely due to
hyperkeratosis rather than
to a mild increase in
melanin pigmentation . A
subtle infiltrate composed
of lymphocytes, plasma
cells, or neutrophils may
be present, as well as horn
pseudocyst formation .
Tissue staining with
colloidal iron often shows
infiltration of the papillary
dermis with
glycosaminoglycans such
as hyaluronic acid,
particularly in patients with
gonadal disease such as
polycystic ovarian
syndrome (PCOS)
Histology of acanthosis
nigricans, demonstrating
papillomatosis and
hyperkeratosis.
(Hematoxylin and eosin,
original magnification
x40).
Skin tags
Skin tags
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Skin tags are common tumors that usually affect middle-aged individuals and the elderly. They usually occur on
the neck, armpits and groin. They are small soft and pedunculated protrusions. The lesions may be brown or skincolored and range from 1mm to 1cm in diameter. Histologically, they are characterized by loss of collagen fibers
and dilated blood capillaries.
Multiple skin tags are frequently found in obese and non-insulin-dependent diabetic individuals; insulin resistance
is an abnormality underlying the two conditions. The proliferation of fibroblasts that occurs in skin tags seems to be
due to hyperinsulinemia, via activation of the insulin-like growth factor (IGF-1) receptors present on their surfaces.
Skin tags are closely related to fasting insulin levels.
In recent years, some studies have tried to show the correlation between skin tags and insulin resistance, their
serum levels and the levels of IGF-1.. Similar to acanthosis nigricans, insulin does not appear to be the only
mediator in the formation of skin tags, but it is certainly the most important one in the formation of these lesions.
In individuals who have multiple skin tags, it is important to suspect of a disorder in the metabolism of
carbohydrates, either in the form of insulin resistance or diabetes mellitus.
No correlation was found between the topography of skin tags and carbohydrate metabolism, except for skin tags
in the inframammary region in women.
Identification of an independent association between presence of more than five skin tags and an increase of 1.4
units in the HOMA-IR index in dermatological patients. The significant association with BMI and
hypertriglyceridemia strengthens the concept that skin tags may constitute markers of insulin resistance. Presence
of skin tags is associated with pregnancy, acromegaly, intestinal polyps, dyslipidemia and several syndromes:
polycystic ovary, Birt-Hogg-Dube and Cowden syndromes. Variations in estrogen levels are implicated in the
etiology of these lesions.
Individuals with skin tags have a high prevalence of thyroid nodules and thyroid with increased volume. This is
because skin tags and thyroid changes may be associated with high levels of circulating insulin.
Skin tags
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Skin tags are very common soft harmless lesions that appear to hang off the skin. They are also described as:
- Acrochordons
- Papillomas
- Fibroepithelial polyps
- Soft fibromas
- Pedunculated (this means they are on a stalk)
-Filiform (this means they are thread-like)
Skin tags develop in both men and women as they grow older. They are skin colored or darker and range in size from 1mm to 5cm. They
are most often found in the skin folds (neck, armpits, groin). They tend to be more numerous in obese persons and in those with type 2
diabetes mellitus.
The surface of an acrochordon may be smooth or irregular in appearance and is often raised from the surface of the skin on a fleshy stalk
called a peduncle. Microscopically, an acrochordon consists of a fibro-vascular core, sometimes also with fat cells, covered by an
unremarkable epidermis. However, tags may become irritated by shaving, clothing, jewellery or eczema. .
Seborrhoeic keratoses, viral warts or molluscum contagiosum may resemble skin tags. ...
causes of skin tags
It is not known what causes skin tags. However, the following factors may play a role:
-Chaffing and irritation from skin rubbing together
- High levels of growth factors, particularly during pregnancy or in acromegaly (gigantism)
- Insulin resistance (syndrome X) Skin tags may serve as a marker for those people whose carbohydrate metabolism is impaired and for
those who may be at risk for diabetes mellitus type 2. Elevated blood sugar and insulin increase the incidence of skin tags through an
unknown mechanism
- Human papilloma virus (wart virus)
How can they be removed?
Skin tags can be removed for cosmetic reasons by the following methods:
- Cryotherapy (freezing)
- Surgical excision (often with scissors)
- Electrosurgery (diathermy)
- Ligation (a suture is tied around the neck of the skin tag)
Skin tags
Acrochordon, pedunculated, fibrous mass covered with epithelium of
varied thickness, H&E stain
Skin tags
Insulin Resistance
Insulin Resistance
• Insulin resistance is a metabolic disorder in
which target cells fail to respond to normal levels
of circulating insulin. Insulin resistance has been
associated with presence of acanthosis
nigricans and acrochordons. It is known that
early diagnosis and early initial treatment are of
paramount importance to prevent a series of
future complications. These dermatoses may
represent an easily identifiable sign of insulin
resistance and non-insulin-dependent diabetes
Insulin Resistance (IR)
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Insulin resistance (IR) is a metabolic disorder in which target cells fail to respond to normal levels of circulating
insulin, which results in compensatory hyperinsulinemia in an attempt to obtain an appropriate physiological
response. It is especially found in individuals with @ diabetes mellitus (DM) type 2,@ decompensated type 1 DM,
@ diabetic ketoacidosis and @obesity. In normal populations, IR occurs in 20 to 25% of the individuals.
There are three types of IR:
(i) Type A, caused by a reduced number and dysfunction of insulin receptors;
(ii) type B, caused by formation of antibodies against insulin receptors; and
(iii) Type C, which corresponds to a post-receptor defect. Obese patients and patients with polycystic ovary
syndrome (PCOS) have type-A insulin resistance.
DM occurs when insulin secretory capacity fails to reduce serum glucose. Insulin concentrations are generally
higher in early type 2 diabetes, but the levels are not enough to compensate for insulin resistance due to a
pancreatic beta cell defect.
Insulin resistance increases during puberty and appears to be related to fat accumulation.
The insulin receptor belongs to the family of tyrosine kinase receptors, which includes the insulin-like growth factor
(IGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor, colonystimulating factor I and several cytokine receptors. A high concentration of insulin results in a direct and indirect
activation of IGF-1 receptors in keratinocytes and fibroblasts, leading to their proliferation. Other mediators can
contribute, including other tyrosine kinase receptors such as EGFR - epithelial growth factor receptor - and FGFRfibroblast growth factor receptor.
Hyperinsulinemia increases ovarian androgen production and IGF-1 and 2 in the liver. Insulin and IGF-I increase
the activity of 17-hydroxylase in the ovaries, causing excessive production of androgens, especially of 17hydroxyprogesterone (17-OHP) . Indirectly, insulin potentiates the action of LH in the ovaries. Another effect of the
increase in insulin levels is a decrease in the hepatic production of SHBG (a sex-hormone carrier protein) and
IGFBP-I (IGF-1 carrier protein or IGF-1 binding protein), contributing to greater action of free testosterone (FT)
and IGF-1, respectively, in target cells. In vitro studies have shown that insulin and IGF-1 may also stimulate
growth of the hair follicle and act together with androgens when playing this role. Hyperinsulinemia can also
increase the action of 5-alpha reductase, leading to increased conversion of testosterone into
dihydrotestosterone.
Insulin Resistance (IR)
Insulin Resistance
• Elevated insulin
concentrations result in
direct and indirect
activation of IGF-1
receptors on
keratinocytes and
fibroblasts, leading to
proliferation. Other
mediators may also
contribute, including other
tyrosine kinase receptors
such as :EGFR and
FGFR. (IGF = insulin-like growth factor, BP
= binding protein, IGF-1R = insulin-like growth
factor 1 receptor, EGFR = epidermal growth factor
receptor, FGFR = fibroblast growth factor receptor)
Insulin Resistance
Insulin Resistance ( IR)
• There are several methods of assessment and diagnosis of
IR. Fasting insulin levels have been used to assess IR, since it is
easy to use this method in large populations. Homeostasis Model
Assessment (HOMA) is a mathematical model that predicts IR by
simply measuring fasting glucose and insulin levels. Also, it has
good correlation with the hyperinsulinemic-euglycemic clamp
method, which is considered the gold standard for the measurement
of IR. Its calculation for IR is done by multiplying the amount of
glucose (in mmol) by the amount of insulin (in uU/mL) and dividing
this result by 22.5 (HOMA-IR = glucose (mmol) x insulin (uU/mL) ÷
22.5). IR is diagnosed when the result is greater than 2.71. In
women, insulin resistance is considered when the result exceeds
the 75th percentile (1.80). Direct methods of assessment of IR
include the insulin tolerance test (KITT), insulin suppression test and
hyperinsulinemic-euglycemic clamp techniques. The costs of their
development, however, limit their use
Pathogenesis of
acanthosis nigricans
Dermatology Online Journal 14 (9): 2
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The true pathogenesis of AN, however, is likely to be more complex. Obese
patients rarely, if ever, achieve levels of insulin high enough (10 nM) to activate
IGF-1Rs . The predilection of AN for areas such as the neck and axillae suggests
that perspiration and/or friction also may be necessary cofactors .
Hyperinsulinemia may also facilitate the development of AN indirectly by increasing
the levels of free IGF-1 in the circulation. The activity of IGF-1 is regulated by IGF
binding proteins (IGFBPs), which increase IGF-1 half life, deliver IGFs to target
tissues, and regulate the levels of the metabolically active "free" IGF-1 . Insulin-like
growth factor 1 binding protein and IGFBP-2 are both decreased in obese subjects
with hyperinsulinemia, increasing plasma concentrations of free IGF-1 . An
increase in bioactive IGF-1 promotes cell growth and differentiation .
Insulin-like growth factor 1 is expressed within the stratum granulosum and by
dermal fibroblasts, but not by epidermal basal keratinocytes . In theory, an insulininduced systemic reduction of IGFBP-1 and IGFBP-2 could increase local levels of
free IGF-1, thereby facilitating the development of hyperkeratosis and
papillomatosis.
Curiously, therapy with IGF-1 has resulted in improvement of extreme insulin
resistance syndromes, including improvement of AN in 5 of 7 patients . Insulin-like
growth factor 1 may reduce serum insulin concentrations and downregulate
expression of IGF-1R . Since insulin binds with lower affinity to the IGF-1 receptor
than IGF-1 itself, it is possible that insulin may be less proficient than IGF-1 at
downregulating IGF-1Rs.
Hyperinsulinemia does not mediate all forms of acanthosis nigricans. As
mentioned previously, certain AN syndromes are due to FGFR defects . Some
malignancies may be associated with insulin receptor antibodies, as in one
reported case of metastatic pheochromocytoma; however, no insulin resistance is
described for most cases of paraneoplastic AN [64]. Malignancy-associated AN
might be explained by elevated levels of growth factors such as transforming
growth factor (TGF-α), which exerts effects on epidermal tissue via the epidermal
growth factor receptor (EGFR) . One patient experienced a decrease in urinary
TGF-α and improvement of AN after resection of a melanoma .
Insulin-like growth factor 1 receptor, FGFR, and EGFR are all tyrosine kinase
receptors and acanthosis nigricans seems to be a final common manifestation of a
variety of processes [4]. The post-receptor intracellular pathways likely converge,
although they have not been fully elucidated [4]. Other perplexing aspects of AN
include its predilection for certain races and anatomic sites, as well as the fact that
only some people with predisposing states develop the condition.
Acanthosis Nigricans
Treatment
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Treatment Guidelines
A.
Correction of underlying cause
Removal of tumor
Correction of endocrine disorder
Reduction of weight
Removal of causative drug
Dietary supplimentation with fish oil containing omega 3 fatty acids have been reported to be beneficial
Regular skin treatment
B.
Management of Skin Lesions:
Topical Retin A
Salicylic acid application alone or in combination with steroids, alternating with emollient applications to minimize irritation.
In severe unresponsive cases, systemic retinoids may be given a trial under the guidance of a dermatologist.
Role of Homoeopathy
Acanthosis nigricans is the cry of the skin for attention! It is a skin disorder characterized by thickening, pigmentation and a fine or rough velvety
appearance, particularly over body folds. It can be caused by a variety of causes.
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Homoeopathy has good scope in treating Acanthosis Nigricans. Homoeopathy will definitely reduce hyperpigmentation by treating underlying cause.
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Homoeopathy recognizes importance of root cause such as genetic and inherited factors as a root of any ailment of the body. Homoeopathy is the only
method which will treat these hereditary tendencies.
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Homoeopathic approach of treatment is holistic. It treats “patient as a whole” not just his specific disease or parts. In homoeopathy, physical and mental
aspects are considered for selection of medicine. Such medicine is known as ‘constitutional medicine’.
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People with acanthosis nigricans are known for their resistance to insulin in diabetics. Homeopathy has a good role to offer in treating diabetes and thus
can treat
Homeopathic medicines detoxify body; as well as raise the natural immunity.
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Homoeopathic medicines work effectively in all age groups and can be taken safely during pregnancy by women.
Homoeopathic medicines are safe, gentle and effective to give relief in harmless way. Homeopathic medicine should be taken after consulting
Homeopathic physician on
A Buddhist monk in Thailand