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Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.

Psoriasis is a chronic inflammatory skin disease characterized by hyperplasia of the epidermis (acanthosis), infiltration of leukocytes into both the dermis and epidermis, and dilation and growth of blood vessels. The underlying cause of the epidermal acanthosis in psoriasis is still largely unknown. Recently, interleukin (IL)-23, a cytokine involved in the development of IL-17-producing T helper cells (T(H)17 cells), was found to have a potential function in the pathogenesis of psoriasis. Here we show that IL-22 is preferentially produced by T(H)17 cells and mediates the acanthosis induced by IL-23. We found that IL-23 or IL-6 can directly induce the production of IL-22 from both murine and human naive T cells. However, the production of IL-22 and IL-17 from T(H)17 cells is differentially regulated. Transforming growth factor-beta, although crucial for IL-17 production, actually inhibits IL-22 production. Furthermore, IL-22 mediates IL-23-induced acanthosis and dermal inflammation through the activation of Stat3 (signal transduction and activators of transcription 3) in vivo. Our results suggest that T(H)17 cells, through the production of both IL-22 and IL-17, might have essential functions in host defence and in the pathogenesis of autoimmune diseases such as psoriasis. IL-22, as an effector cytokine produced by T cells, mediates the crosstalk between the immune system and epithelial cells.

Animals↗

Acanthosis nigricans and the sign of Leser-Trélat associated with adenocarcinoma of the gallbladder.

A case of adenocarcinoma of the gallbladder associated with acanthosis nigricans and the sign of Leser-Trélat is presented. The significant underrepresentation of adenocarcinoma of the gallbladder in association with malignant acanthosis nigricans is noted. If malignant acanthosis nigricans is caused by an ectopic peptide, a relative lack of production of the postulated substance by gallbladder adenocarcinoma cells could account for this finding.

Acanthosis Nigricans↗

Transforming growth factor-alpha (TGF alpha)-producing gastric carcinoma with acanthosis nigricans: an endocrine effect of TGF alpha in the pathogenesis of cutaneous paraneoplastic syndrome and epithelial hyperplasia of the esophagus.

A case of well-differentiated adenocarcinoma (Borrmann type 3) of the stomach in a 76-year-old man associated with the typical skin manifestations of acanthosis nigricans and with multiple protruding lesions showing epithelial hyperplasia of the esophagus is reported. The advanced tumor was located in the cardiac region of the stomach, and measured approximately 8 cm in diameter, with partial invasion to the esophagus. The associated cutaneous lesions were characterized by hyperpigmentation and by protruding verrucous papules on the torso, head, face, neck, upper extremities, perineum, and inguinal region. Histologically, the protruding skin lesions showed keratinocytes proliferation throughout the epidermis, resulting in diffuse hyperkeratosis, papillomatosis, and acanthosis of the skin. Immunohistological analysis showed coexpression of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) receptors in the tumor from the stomach. It is reasonable to conclude from this evidence that gastric carcinoma cells secrete TGF alpha in an autocrine for auto-stimulation. EGF receptor expression was also noted on the papillomatous hyperplasia of the cutaneous lesion. Serum level of TGF alpha, determined by an enzyme-linked immunosorbent assay, was high (144 pg/ml; normal, 22.0 +/- 16 pg/ml (Mean +/- SD)). Serum TGF alpha abruptly decreased to 49 pg/ml on day 7 after the total gastrectomy, and then gradually increased to 77 pg/ml within 28 days. Amelioration of the cutaneous lesions and the protruding lesions in the esophagus was observed after surgical resection of the gastric carcinoma. This suggests that the TGF alpha stimulates the proliferation of keratinocytes involved with EGF receptor. Large amounts of circulating TGF alpha in the blood over a long period released by the primary tumor seem to act as an endocrine-like mechanism causing epidermal and esophageal epithelial cells to proliferate. There is a possible link in the pathogenesis of the acanthosis nigricans as a cutaneous paraneoplastic syndrome, and epithelial hyperplasia of the esophagus.

Acanthosis Nigricans↗

Long-term octreotide treatment reduced hyperinsulinemia, excess body weight and skin lesions in severe obesity with acanthosis nigricans.

A boy affected by severe obesity (kg 117, Body Mass Index 37 kg/m2) and acanthosis nigricans, was treated with octreotide for 150 days (50 micrograms x three daily subcutaneous administrations). Before treatment the patient showed an exaggerated insulin (IRI) and C-peptide (CPR) response to a standard meal with a lowering in after-meal CPR/IRI molar ratio. During octreotide treatment both IRI and CPR response was reduced but CPR/IRI molar ratio rised after meal indicating an increase in hepatic insulin removal. Body weight and acanthosis nigricans were sharply reduced during treatment and the reduction was still maintained six months after the cessation of therapy. Furthermore, IRI and CPR response, as well as the behaviour of CPR/IRI molar ratio, remained within normal range. In conclusion long-term octreotide treatment has been able to correct hyperinsulinemia and to reduce body weight and acanthosis nigricans.

Acanthosis Nigricans↗

[Acanthosis nigricans associated with transitional cell carcinoma of the bladder--symptomatic treatment with calcipotriol].

Acanthosis nigricans is a hyperkeratotic mucocutaneous eruption of heterogenous etiology which is characterized by hyperpigmentation, velvety cutaneous thickening, intensified skin markings and development of verrucous excrescences typically involving the intertriginous areas. Malignant acanthosis nigricans is most often associated with an abdominal adenocarcinoma frequently unresectable at the time of diagnosis. We report on the rare association of acanthosis nigricans with a transitional cell carcinoma of the urinary bladder. Symptomatic treatment with topical calcipotriol significantly reduced the hyperkeratotic and papillomatous skin changes.

Acanthosis Nigricans↗

Acanthosis nigricans in Kabuki syndrome.

BACKGROUND: Acanthosis nigricans has been classified in different ways. All classifications depend on the clinical picture and the association with other conditions. OBJECTIVE: We report a case of acanthosis nigricans in a patient with Kabuki syndrome. This syndrome is characterized by five main manifestations: typical facial features, post natal growth deficiency, skeletal abnormalities, dermatoglyphic abnormalities, and mild to moderate mental retardation. CONCLUSION: Our case may suggest that acanthosis nigricans could be associated with Kabuki syndrome.

Abnormalities, Multiple↗

Microscopic acanthosis nigricans in type 2 diabetes.

BACKGROUND: Acanthosis nigricans (AN) has been associated with insulin resistance. Individuals with type 2 diabetes are insulin-resistant and, therefore, could be expected to manifest AN. However, the prevalence and predictors of AN are unknown in this population. OBJECTIVE: An outpatient population with Type 2 diabetes (DM) was compared with matched controls (C) for microscopic and clinical AN along with measurement of body habitus, insulin, glucose, and androgen levels. METHODS: Twenty-four individuals with DM (12M, 12F) from a tertiary care center were compared with 24 C (12M, 12F). Fasting glucose, insulin, sex hormone binding globulin, androstenedione, dihydroepiandrosterone sulfate, and testosterone were measured. Height, weight, waist/hip measures, and a clinical survey for acanthosis were recorded. A 2-mm skin biopsy from midaxilla of the nondominant arm was taken for pathological review. RESULTS: C and DM were matched for age and body mass index (BMI). Prevalence of microscopic AN in C was 12% (3/24) and in DM was 21% (5/24; NS). In C, AN was predicted by waist, waist/hip ratio, and fasting insulin measures, while none of the variables examined was predicative of AN in DM. CONCLUSIONS: Microscopic acanthosis nigricans was found in similar numbers of people with DM when compared with C. Fasting insulin levels most strongly predicted the presence of AN in C, while no significant predictors of AN were found in the population with DM.

Acanthosis Nigricans↗

Impaired insulin degradation in a patient with insulin resistance and acanthosis nigricans.

The kinetics of plasma insulin were studied in a 14 year old girl with the syndrome of insulin resistance and acanthosis nigricans. The clearance of plasma insulin was found to be strikingly reduced (135 ml/min . m2 versus 456 +/- 22 in 17 normal control subjects), whereas the basal systemic insulin delivery rate was increased about 10-fold (25.5 mU/min . m2 versus 2.6 +/- 0.3 in normal subjects). Thus, reduced insulin clearance and excessive posthepatic delivery of the hormone both contributed to the severe fasting hyperinsulinemia (218 microunits/ml) associated with the other clinical features of the syndrome (glucose intolerance, primary amenorrhea, polycystic ovaries, hirsutism). Following ovarian wedge resection, insulin clearance rose to 264 ml/min . m2, and insulin delivery fell to 9.8 microunits/ml min . m2. The resulting abatement of the patient's hyperinsulinism (fasting plasma insulin = 37 microunits/ml) was accompanied by the appearance of menses, normalization of glucose tolerance, and amelioration of the acanthosis. The improvement in menstrual function and acanthosis, however, was not sustained. This case provides evidence for interdependence of insulin action and insulin degradation in humans.

Acanthosis Nigricans↗

Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features.

The HAIR-AN syndrome that consists of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) is an underdiagnosed endocrinopathy, because hyperandrogenic women are not commonly screened for insulin resistance or acanthosis nigricans. The distinct pathophysiologic features of the HAIR-AN syndrome are discussed in detail. In this syndrome, the primary pathophysiologic derangements are the insulin resistance and the hyperandrogenism. The acanthosis nigricans is an epiphenomenon of these primary processes. In patients with the HAIR-AN syndrome, the degree of severity of the insulin resistance is positively correlated with the degree of severity of the hyperandrogenism. In patients with adequate pancreatic beta-islet cell reserve, insulin resistance results in a long-term increase in circulating insulin levels. The hyperinsulinemia probably directly stimulates ovarian androgen production. In turn, hyperandrogenism itself produces insulin resistance. This positive feedback loop between insulin resistance and hyperandrogenism propagates the disease, and increases its severity over time. The relationship between insulin resistance and hyperandrogenism may explain the hyperandrogenemia seen in the following disease processes: obesity, acromegaly, lipoatrophic diabetes, leprechaunism, and Kahn types A and B insulin resistance.

Acanthosis Nigricans↗

Insulin resistance with acanthosis nigricans: the roles of obesity and androgen excess.

The roles of hyperandrogenemia and obesity in the syndrome of severe insulin resistance with acanthosis nigricans were evaluated in studies of 11 females with this condition. Our results in these subjects were compared to evaluations of control subjects matched for degree of androgen excess or obesity. Fasting insulin levels were 3-, 5-, and 15-fold higher in the obese (OB), hyperandrogenemic (HO), and acanthosis nigricans (AN) groups, respectively, when compared to normal females. Responsiveness to a standard bolus of exogenous insulin was 78% of normal in the OB group, 40% of normal in the HO group, and 30% of normal in the AN group. Insulin binding to monocytes from both the OB group, and the HO group was modestly diminished primarily due to decreased receptor number. As a group, AN subjects when compared to either normal or weight-matched controls, demonstrated a significant decrease in monocyte insulin binding predominantly due to a decrease in receptor number. However, two patients in the AN group had normal insulin binding suggesting a postreceptor mechanism for the insulin resistance in at least some of these subjects. In vivo glucose utilization insulin dose response curves were determined in 3 acanthotic subjects using the euglycemic clamp technique. All 3 of these subjects had a right shift of the curve and diminished maximal utilization, consistent with combined receptor and postreceptor defects in insulin action. In evaluating the relationship between hyperandrogenemia, insulin resistance, and acanthosis nigricans, significant correlations among basal levels of plasma insulin, and both testosterone and androstenedione were demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Acanthosis Nigricans↗

The role of chronic acanthosis and subacute inflammation in tumor promotion in CD-1 mice by petroleum middle distillates.

An initiation-promotion bioassay using CD-1 mice was conducted to examine the role of chronic acanthosis and inflammation in tumor promotion by petroleum middle distillates (MD). Test groups were initiated with 7,12-dimethylbenz[a]anthracene (DMBA). Promotion with MD consisted of twice weekly treatments for 25 weeks with either 25 or 50 microliters, 50 microliters + daily treatment with 15 micrograms dexamethasone, 50 microliters + postapplication washings, or 100 microliters. Three mice from each group were euthanized at 21-day intervals (24 total per group). The skin from interim euthanized mice was examined histopathologically for tumors, acanthosis, and subacute inflammation. Tumor incidence at study termination was as follows: 25 microliters (45%), 50 microliters (43%), 50 microliters + dexamethasone (0%), 50 microliters + washing (70%), and 100 microliters (81%). A correlation of greater than 0.93 was observed at all intervals between tumor incidence and cumulative group mean degrees of acanthosis in interim euthanized mice. The correlation between subacute inflammation at early through midstudy interval weeks and tumor incidence at study termination was poor. These results support the hypothesis that induction of a lasting, albeit mild, hyperplasia is an essential, but not sufficient requirement for tumor promotion. Furthermore, subacute inflammation does not appear to be a significant factor in tumor promotion by petroleum MD.

9,10-Dimethyl-1,2-benzanthracene↗

Acanthosis nigricans--decreased extracellular matrix viscosity: cancer, obesity, diabetes, corticosteroids, somatotrophin.

Acanthosis nigricans is a reaction pattern to over a dozen different causes. The skin, most classic in the axilla, is dark, soft, velvet-like with fine folding and papillae. The mechanism of this skin change is decreased viscosity of extracellular matrix (ECM) combined with mechanical extrusion of ECM into papillae extending out from the upper dermis. It occurs in obesity (increased mechanical pressure on ECM), diabetes (decreased quality of glycosaminoglycans) (GAG), excess corticosteroids (decreased quality of GAG), pineal tumors (increased ECM and edema), other endocrine disorders (alterations in the quality of GAG), multiple genetic variants (structural and chemical change), from drugs such as nicotinic acid, estrogens, corticosteroids (weakened or altered GAG) and adenocarcinoma (fractions of depolymerized or altered GAG released from the tumor area are incorporated into and weaken the skin GAG). Acanthosis nigricans was first reported in 1890 as a cutaneous sign of internal malignancy. Acanthosis nigricans presents an opportunity to better understand what is occurring in the ECM in many disorders. The understanding of the association of AN and internal malignancy will expand our understanding of how a neoplasm decreases generalized ECM viscosity.

Acanthosis Nigricans↗

Elevated serum dehydroepiandrosterone sulfate levels in patients with insulin resistance, hirsutism, and acanthosis nigricans.

The association of insulin resistance, hyperandrogenism, and acanthosis nigricans is well established. The ovary is thought to be the site of the excess androgen production. The purpose of this study was to assess the adrenal contribution to the hyperandrogenic state in these women. Twenty-three patients presenting with the combination of hyperinsulinemia, elevated testosterone (T) levels, and acanthosis nigricans were investigated for the source of the increased androgen production. Twelve patients had elevated serum dehydroepiandrosterone sulfate (DS) levels (high DS group) suggestive of increased adrenal androgen production. Eleven patients had normal DS levels (normal DS group). Both normal DS and high DS groups had similar basal serum insulin levels and similar insulin response curves after a 3-hour, 75-gm, oral glucose tolerance test. No correlation was found between serum T or DS levels and either basal serum insulin levels or the area under the insulin response curve. These data suggest that DS levels are frequently elevated in patients with hirsutism, acanthosis, and hyperinsulinemia. Furthermore, the lack of association between serum DS and serum insulin levels suggests that insulin does not directly affect adrenal androgen production, or vice versa.

Acanthosis Nigricans↗

Malignant acanthosis nigricans. A case report.

PURPOSE: The authors present a case of malignant acanthosis nigricans that has two unusual aspects. The first is involvement of the lid margins with confluent papillomata, causing severe visual impairment, and the second is the association with lung malignancy. METHODS: A 65-year-old Portuguese man presented with decreased vision, papillomatous lid lesions, pruritus, and progressive thickening of the skin of his face, neck, axillae, and inguinal creases. A diagnosis of acanthosis nigricans was made after skin biopsy. Systemic investigations showed a suprahilar mass, and biopsy was positive for squamous cell carcinoma of the lung. RESULTS: The patient underwent excision of papillomata from all four lid margins, and this was repeated 1 year later. He also completed a course of palliative radiotherapy. CONCLUSION: Malignant acanthosis nigricans is rarely associated with lung neoplasms, being more commonly a manifestation of intra-abdominal malignancies. Of note in this case is the extensive ocular involvement and visual impairment.

Acanthosis Nigricans↗

Hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome: spontaneous remission in a 15-year-old girl.

Acanthosis nigricans is associated with many diseases, including internal malignancies, genetic disorders, and endocrine abnormalities. Insulin resistance frequently accompanies endocrine-associated acanthosis nigricans. We describe a patient with acanthosis nigricans associated with hyperandrogenism and extreme insulin resistance that spontaneously resolved after a marked decrease in insulin receptor antibodies.

Acanthosis Nigricans↗

Malignant acanthosis nigricans with florid papillary oral lesions.

Acanthosis nigricans is a distinctive skin disease of importance, because it has served as an external marker for a variety of systemic disorders including endocrinopathies, and malignant tumors of internal organs. It typically appears as hyperpigmented, roughened plaques of velvety consistency and infrequently as verruca-like papillations. The oral cavity and lips can be affected by florid papillary growths. Because of its rarity and nonspecific microscopic appearance, clinical recognition of acanthosis nigricans continues to be a challenge. A case of mucocutaneous "malignant" acanthosis nigricans is presented in which pigmented skin lesions led to the discovery of a gastric adenocarcinoma, which in turn was followed by the appearance of massive oral papillomatosis. No effective treatment was found.

Acanthosis Nigricans↗

[Metabolic alterations related to syndrome X and low vitamin E levels in obese children with acanthosis nigricans].

BACKGROUND: In adults, both metabolic alterations related to syndrome X and lower plasma vitamin E levels have been associated with an increased risk of developing cardiovascular disease. OBJECTIVES: To study the presence of metabolic alterations related to syndrome X and to determine the plasma levels of vitamin E in obese children with acanthosis nigricans. METHODS: We performed a prospective study in 42 obese children [15 with acanthosis nigricans (AN) and 27 without]. Thirteen healthy non-obese children were also studied. After a 12-hour fast, plasma levels of glucose, insulin, triglycerides, cholesterol, high-density lipoprotein (HDL)-cholesterol, and vitamin E were determined. The insulin resistance index was also calculated. Differences between groups were determined using ANOVA. RESULTS: Obese children with AN showed higher plasma levels of insulin and triglycerides and lower plasma levels of HDL-cholesterol and vitamin E, as well as a higher insulin resistance index than non-obese children and obese children without AN. CONCLUSIONS: In obese children, the presence of acanthosis nigricans is linked to a group of metabolic alterations associated with a higher risk of developing cardiovascular disease and type 2 diabetes.

Acanthosis Nigricans↗

Malignant acanthosis nigricans: potential role of chemotherapy.

Acanthosis nigricans is an uncommon skin condition characterized by hyperkeratosis and skin hyperpigmentation. Most causes are benign, but it may also be associated with gastrointestinal and other malignancies. When associated with malignant disease, the skin pathology may be more severe and treatment often unsuccessful. We describe a 66-year-old man with acanthosis nigricans associated with carcinoma of the stomach, with distressing generalized cutaneous, perioral and perineal disease, whose skin condition resolved completely with combination chemotherapy. In patients with malignant acanthosis, chemotherapy may relieve many of the distressing cutaneous symptoms. A close liaison between gastroenterologists, dermatologists and oncologists is required.

Acanthosis Nigricans↗