Learn about the causes and symptoms of acanthosis nigricans, its association with insulin resistance and obesity.

Acanthosis Nigricans

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Iqra Mazhar

Overview

Acanthosis nigricans (AN) is a common skin pigmentation disorder. The condition is distinguished by dark patches of skin with a thick, velvety texture. It usually has an impact on the armpits, groin, and neck. 
The skin condition causes light-brown to black spots. It frequently presents itself in otherwise healthy individuals, but it can be a sign of a more severe condition. 
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The prevalence of AN is directly related to <a href="https://merisehat.pk/disease/obesity">obesity </a>and <a href="https://merisehat.pk/disease/diabetes-type-1-and-2">diabetes</a>. The frequency of cases ranges from 7-74% depending on age, race, recurrence, the extent of obesity, and concomitant endocrinopathy.

Native Americans are the most likely to have it, followed by African Americans, Hispanics, and Caucasians. One research found that AN was more widespread in black women than in white women. Moreover, malignant AN was found to be less common. In kids, the neck is the most commonly affected site (99%), followed by the axillae (73%)<a href="#accordion">[1]</a>.

AN is more common in people under 40 and is linked to obesity, <a href="https://merisehat.pk/disease/polycystic-ovary-syndrome-pcos">polycystic ovary disease</a>, <a href="https://merisehat.pk/disease/hypothyroidism">hypothyroidism</a>, insulin-resistant diabetes, acromegaly, Cushing disease, and <a href="https://merisehat.pk/disease/addisons-disease">Addison&rsquo;s disease</a><a href="#accordion">[2]</a>. In rare cases, the skin condition may indicate cancer in an internal organ, for example, the stomach or liver. 
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The following are the different types of AN based on the causative factors<a href="#accordion">[1]</a> <a href="#accordion">[2]</a>: 
&nbsp;

<h5>Obesity-Associated Acanthosis Nigricans</h5>

Obesity is the leading cause of AN. AN affects at least 50% of adults who weigh more than 200% of their ideal body weight. It was once also known as &quot;pseudo-acanthosis nigricans.&quot; It can also be due to insulin resistance which often affects obese people.

Lesions can develop at any age, but they tend to occur more frequently in adulthood. These lesions are weight dependent, with the skin returning to normal after weight loss. 
&nbsp;

<h5>Medication-Associated Acanthosis Nigricans</h5>

AN can be a side effect of several medicines that promote hyperinsulinemia. The examples are:

<ul>
	<li>Nicotinic acid</li>
	<li>Systemic steroids</li>
	<li>Diethylstilbestrol</li>
	<li>Oral contraceptive pill</li>
	<li>Growth hormone therapy</li>
	<li>Estrogen</li>
	<li>Protease inhibitors</li>
	<li>Niacin</li>
	<li>Injected insulin 
	&nbsp;</li>
</ul>

Lesions degenerate once the medication with the harmful side effects is stopped. Erickson et al. first characterized acanthosis nigricans as a rare local cutaneous side-effect of insulin injection. Using the right insulin and appropriate technique will help prevent the development of AN<a href="#accordion">[2]</a>. 
&nbsp;

<h5>Familial Acanthosis Nigricans</h5>

It can result from an autosomal dominant trait that manifests at birth or during childhood. Mutations in the fibroblast growth factor receptor 3 gene trigger it. The condition frequently advances until puberty, after which it either stabilizes or degenerates. 
&nbsp;

<h5>Acanthosis Nigricans Associated With Endocrine Dysfunction</h5>

It&rsquo;s rare, has a slower onset, and usually occurs in obese people. Insulin-resistance syndromes are classified as Type A syndrome hyperandrogenism IR or Type B.

Females with uncontrolled diabetes, ovarian hyperandrogenism, or autoimmune diseases such as SLE, Sjogren&#39;s syndrome, or scleroderma are more likely to develop Type B syndrome. 
&nbsp;

<h5>Acral Acanthotic Anomaly</h5>

It happens in healthy people who have no underlying health-related issues. Lesions on the dorsal aspects of the hands and feet are most common in people with dark skin (e.g., African Americans). 
&nbsp;

<h5>Malignant Acanthosis Nigricans Syndrome</h5>

It has been linked to gastrointestinal adenocarcinomas and genitourinary cancers, like prostate, breast, and ovary. Lung cancer and lymphoma are rarely linked to AN. Internal cancer may be preceded, accompanied, or followed by malignant AN. 
&nbsp;

AN caused by cancer usually appears suddenly and is accompanied by skin tags, multiple seborrheic keratoses (a sign of Leser-Trelat), or tripe palms. 
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<h5>Benign Genetic Acanthosis Nigricans</h5>

It is a rare autosomal dominant disorder that appears at birth or develops during childhood without endocrinopathy.

It is associated with adenocarcinomas of the abdominal organs (70-90%), specifically gastric cancer (55-61%), followed by adenocarcinomas of the pancreas, ovary, kidneys, bladder, bronchi, thyroid, bile duct, breast, and esophagus. Onset may be linked to medicine. Lesions may develop on the oral, nasal, and laryngeal mucosa, esophagus, and areola<a href="#accordion">[1]</a>. 
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<h5>Auto-Immune Acanthosis Nigricans</h5>

The development of antibodies to insulin receptors in autoimmune conditions, for example, systemic lupus erythematosus, Sjogren&#39;s syndrome, scleroderma, or Hashimoto&#39;s thyroiditis, cause it. 
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<h5>Unilateral Acanthosis Nigricans</h5>

It is also known as nevoid AN. It is extremely uncommon and inherited in an autosomal dominant manner. Lesions appear unilaterally and can appear during infancy, childhood, or adulthood. They appear on the face, scalp, chest, and abdomen, particularly the periumbilical area, back, and thigh, and can grow slowly before stabilizing or degenerating. 
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<h5>Mixed-Type Acanthosis Nigricans</h5>

It occurs when an individual with one of the types mentioned earlier develops a new AN lesion of a different cause. For example, an overweight patient with obesity-associated AN develops malignant AN afterward. 
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Signs and Symptoms

AN can manifest anywhere on the body. It is most commonly found in the armpits and groin, but can also appear in other areas, such as the back of the neck, face, lips, mucous membranes of the oral cavity, elbows, knuckles, palms, nipples, areolae, navel, knees, and soles of the feet. 
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Following are the signs and symptoms of this skin condition:

<ul>
	<li>Brown or black skin patches</li>
	<li>Skin has a velvety texture</li>
	<li>Dryness</li>
	<li>Skin tags</li>
	<li>Itchiness</li>
	<li>Bad-smelling skin patches</li>
	<li>Nail changes 
	&nbsp;</li>
</ul>

Symptoms usually appear gradually over months or even years. Consult a dermatologist if these symptoms appear quickly as it can be an indication of cancer. Additionally, they may be more widespread and noticeable. 
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Causes

AN can be caused by the following: 
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<h5>Insulin Resistance</h5>

An excess of insulin in the bloodstream is the most common cause of AN. Insulin is a pancreatic hormone that permits the body to process sugar.

Overweight or obese individuals are more likely to develop insulin resistance over time. Although the pancreas produces insulin, the body cannot use it effectively. It causes an accumulation of glucose in the bloodstream, which can result in elevated blood glucose levels and insulin.

Excess insulin stimulates the reproduction of skin cells. These new cells contain more melanin in individuals with darker skin &mdash; the increase in melanin results in a darker skin patch than the skin around it.

Insulin resistance leads to type 2 diabetes and polycystic ovarian syndrome. 
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<h5>Specific Medications And Supplements</h5>

Some medications can also cause it:

<ul>
	<li>Thyroid medications</li>
	<li>Some bodybuilding supplements</li>
	<li>Birth control pills</li>
	<li>Systemic glucocorticoids</li>
	<li>Protease inhibitors</li>
	<li>Diethylstilbestrol</li>
	<li>Human growth hormones</li>
	<li>Estrogen</li>
	<li>Injected supplementary insulin</li>
	<li>Nicotinic acid</li>
</ul>

All of these medications have the potential to alter insulin levels. When a person stops taking the medications, their condition begins to improve. 
&nbsp;

<h5>Cancer</h5>

A few kinds of cancer can trigger acanthosis nigricans. Lymphoma and cancers of the stomach, colon, and liver are among them. 
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<h5>Additional Causes</h5>

In rare instances, acanthosis nigricans can develop because of the following reasons:

<ul>
	<li>Disorders of the pituitary gland</li>
	<li>Low levels of thyroid hormones</li>
	<li>Genetics and family history of AN</li>
	<li>Ethnicity; being of African, Hispanic, Native American, or Caribbean descent</li>
	<li>High doses of niacin</li>
	<li>Stomach cancer</li>
	<li>Adrenal gland disorders, for example, Addison&#39;s disease</li>
	<li>A few autoimmune disorders, like Sj&ouml;gren&#39;s disease or Hashimoto&#39;s thyroiditis 
	&nbsp;</li>
</ul>

Diagnosis

Medical professionals clinically identify and confirm AN with a skin biopsy, i.e., by taking a skin tissue specimen. Diabetes or cancer can necessitate further testing through blood tests, endoscopy, or X-rays.

Spectroscopic and colorimetric measurements, in conjunction with chemometric analysis methods, allow for a sensitive and distinct evaluation of acanthosis nigricans. Doctors advise screening for diabetes and measuring glycosylated hemoglobin since most cases are linked with insulin resistance or obesity.

They may also analyze the current medicines to check if they contribute to the condition. This includes dietary supplements, vitamins, or bodybuilding supplements in addition to prescription medicines. 
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Treatment

Currently , there is no specific treatment for Acanthosis nigricans.

Treatment of the underlying disease or tumor, cessation/avoidance of the inciting agent in drug-induced AN, topical/oral agents, and cosmetic surgery are all part of the therapeutic approach. Since the majority of patients seek treatment solely for cosmetic reasons, the doctor may recommend pain and odor relief treatments, for example, skin creams, specific soaps, medications, and laser therapy.

Treating the underlying cause may be beneficial. Here are some examples: 
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<h5>Cosmetic Treatments</h5>

Among the treatments are:

<ul>
	<li>Skin lighteners, such as Retin-A, 20 percent urea, alpha hydroxy acids, and salicylic acid</li>
	<li>Laser therapy</li>
	<li>Alexandrite laser</li>
	<li>Dermabrasion</li>
	<li>Oral acne medications</li>
	<li>Chemical peels 
	&nbsp;</li>
</ul>

These treatments can help to improve the appearance of AN but will not treat it.

A study on whether a long-pulsed alexandrite laser targeting the melanin in hair could help with this condition recorded 95% clearance of axillary AN following 7 sessions. It concluded that a long-pulsed alexandrite laser can safely and effectively cure axillary AN<a href="#accordion">[1]</a>. 
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NOTE: Consult a healthcare professional before using any skin care products to cure dark spots. These products may not be suitable for all skin types and can exacerbate the problem. 
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<h5>Surgical Treatment</h5>

If a cancerous tumor causes AN, removing the tumor usually cures the skin symptoms. 
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<h5>Topical Treatment</h5>

It includes the following<a href="#accordion">[1]</a>: 
&nbsp;

Retinoids

Topical retinoid is first-line therapy, particularly for unilateral nevoid AN. It treats hyperkeratosis and almost completes the reversion of the condition. 
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Ammonium Lactate And Tretinoin

Lactic acid acts as a peeling agent as well as through the release of desmogleins, indicating the breakdown of desmosomes. The precise mechanism of action of the two agents is unknown; however, it&rsquo;s believed that synergistic interaction plays a role. 
&nbsp;

Peels

Trichloroacetic acid (TCA) is a chemical exfoliant that helps with the repair and rejuvenation of the epidermis. It is safe, readily available, inexpensive, and simple to prepare. TCA 15% is a relatively safer and more effective therapeutic modality for AN compared to other topical treatments. 
&nbsp;

Calcipotriol

Calcipotriol is yet another effective treatment for AN. It suppresses keratinocyte growth. A study described that it is harmless and well-tolerated, another possible treatment for AN when an etiological treatment is not feasible or required<a href="#accordion">[1]</a>. 
&nbsp;

<h5>Oral Treatment</h5>

It includes the following<a href="#accordion">[1]</a>: 
&nbsp;

Oral Retinoids

Oral retinoids (e.g., isotretinoin, acitretin) can be effective; improvement needs high doses and long courses, while recurrence has also been reported. The mechanism of action is believed to be the normalization of epithelial growth and differentiation is likely. While oral isotretinoin has been used conveniently to cure severe AN, acitretin has rarely been effective that too in the case of syndromic and benign AN only. 
&nbsp;

Metformin And Rosiglitazone

Metformin and rosiglitazone are effective treatments in AN with insulin resistance. A study found that while they both slightly improved skin texture, rosiglitazone also reduced fasting insulin levels<a href="#accordion">[1]</a>. 
&nbsp;

Other

An individual can also take the following measures: 
&nbsp;

Lose Weight

Nutritional counseling and weight loss may be beneficial if the AN is triggered by obesity. Weight loss and exercise have been shown to improve obesity-related AN by increasing insulin sensitivity and decreasing insulin levels. 
&nbsp;

Stop Taking Medications

If the condition appears to be associated with a medicine or supplement, a doctor may advise the patient to stop taking it. 
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The potential problems of acanthosis nigricans depend on the underlying cause because the condition is not an isolated disease.

An individual is at risk of developing diabetes-related issues if their insulin levels have increased, which is frequently the case with AN. Complications include eyesight issues and nerve damage.

Also, AN usually takes months or even years to develop fully. Therefore, a sudden or quick start may be a symptom of cancer. If a spot has developed, it&#39;s crucial to contact a dermatologist to explore it further. 
&nbsp;

Obese people are more likely to develop AN. Additionally, those who have a family history of the ailment are at a higher risk, particularly if obesity and type 2 diabetes run in the family. 
&nbsp;

Generally speaking, leading a healthy lifestyle can help a person avoid AN: 
&nbsp;

<ul>
	<li>Keep a healthy weight</li>
	<li>Modify any medications that are making the condition worse</li>
	<li>Consume a healthy diet 
	&nbsp;</li>
</ul>

Acanthosis Nigricans Is A Strong Predictor Of Low Blood Calcidiol Levels In Children And Adolescents.<a href="#accordion">[3]</a> Obesity and metabolic syndrome are risk factors for low Vitamin D levels and are also associated with AN. The study explored whether the clinical diagnosis of AN can be a strong predictor for vitamin D deficiency (VDD) in children.

The results showed that the risk of developing VDD was 3.6 times higher in people with AN than those without AN and that males were 0.41 times less likely than females to have AN.

Consequently, it was suggested that low calcidiol levels should probably be checked in children and adolescents with AN as they are more likely to develop VDD. 
&nbsp;

Key Points

<ul>
	<li>Acanthosis Nigricans is characterized by thick, velvety patches of dark skin.</li>
	<li>These patches can also itch or smell.</li>
	<li>Acanthosis Nigricans may manifest before birth or in infancy with a genetic connection. However, it is most frequently linked to obesity and an insulin-resistant condition. 
	&nbsp;</li>
</ul>

[1] Phiske MM. An approach to acanthosis nigricans. Indian Dermatol Online J. 2014;5(3):239.

[2] Brady MF, Rawla P. Acanthosis nigricans. 2017;

[3] Isart FA, Isart-Infante FJ, Heidel ER, Sisley S. Acanthosis Nigricans Is a Strong Predictor of Low Blood Calcidiol Levels in Children and Adolescents. Metab Syndr Relat Disord. 2022;20(9):509–16.

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