Miscellaneous Inflammatory Diseases

## **Chapter 14** Non-Allergic Rhinitis

*Erkan Yildiz*

### **Abstract**

Non-allergic rhinitis is a term used for situations where no allergen can be detected as the cause of rhinitis. In non-allergic rhinitis; Skin test positivity or specific Ig E response cannot be detected. The pathophysiology of nonallergic rhinitis (NAR) is heterogeneous. The most common type is vasomotor rhinitis, also called idiopathic. In addition, there are many types such as hormonal, gustatory, occupational, atrophic, cold air-induced and systemic diseases. Patients; They present with symptoms such as nasal congestion, runny nose, sneezing, and itching in the nose, the symptoms of the patients do not show a seasonal pattern. There are family stories, but they are not as common as allergic rhinitis (AR). An underlying factor such as infection, sinusitis or polyps cannot be detected in patients. It was determined that the patients showed more neurogenic abnormalities in the pathophysiology. These patients have been shown to be hypersensitive to substances with ingredients such as cold air or capsaicin. The diagnosis is made clinically, the onset of the disease is in adolescence. Oral/nasal antihistamines, steroids, leukotriene antagonists are used in the treatment.

**Keywords:** non-allergic rhinitis, IgE, vasomotor rhinitis, eosinophilic nonallergic rhinitis, rhinitis medicomentosa

### **1. Introduction**

#### **1.1 Non-allergic rhinitis**

Non-allergic rhinitis is a term used for situations where no allergen can be detected as the cause of rhinitis. Non-allergic rhinitis occurs in approximately one third of allergic rhinitis. Affects 22 million people (7% of the population) in the USA [1]. In non-allergic rhinitis; Skin test positivity or specific Ig E response cannot be detected. The pathophysiology of nonallergic rhinitis (NAR) is heterogeneous [2]. The most common type is vasomotor rhinitis, also called idiopathic. In addition, there are many types such as hormonal, gustatory, occupational, atrophic, cold air-induced and systemic diseases [3]. Patients; They present with symptoms such as nasal congestion, runny nose, sneezing, and itching in the nose, the symptoms of the patients do not show a seasonal pattern. There are family stories, but they are not as common as allergic rhinitis (AR). An underlying factor such as infection, sinusitis or polyps cannot be detected in patients. It was determined that the patients showed more neurogenic abnormalities in the pathophysiology. These patients have been shown to be hypersensitive to substances with ingredients such as cold air or capsaicin. The diagnosis is made clinically, the onset of the disease is in adolescence [4].

#### **2. Pathophysiology**

Non-Allergic rhinitis occurs due to non-IgE mediated mechanisms. Prostaglandins, leukotrienes are found in both the upper and lower airways. These cause mast cell secretion, eosinophils, after exposure to the allergen in rhinitis. Prostaglandins and leukotrienes released from mast cells cause vasodilatation and hypersecretion from the gland, leading to rhinitis symptoms. Although this mechanism is not fully active in non-allergic rhinitis, symptoms occur with a similar effect [5].

#### **3. Vasomotor rhinitis**

Vasomotor rhinitis; It constitutes the most important part of rhinitis in the definition of non-allergic rhinitis. Its other name is known as non-allergic rhinopathy. It occurs as a result of impaired vasomotor balance in the nose. There is a loop in the form of sympathetic/parasympathetic innervation in the nose. This cycle is disrupted due to reasons such as exercise, cold, stress, insufficient thyroid functions, pregnancy, excessive or prolonged use of some blood pressure drugs, birth control pills and decongestant drugs. At the beginning of all these reasons, nasal congestion is temporary and reversible. So if the cause is removed, the disease will improve. In addition, if it lasts long enough, this time the blood vessels will lose their elasticity and the event turns into an irreversible situation. Metabolic (Acromegaly, Pregnancy, Hypothyroidism), Autoimmune (Sjogren's syndrome SLE Relapsing polychondritis Churg-Straus),Granulomatous diseases (Sarcoidosis and Wegener's granulomatosis), Other (Cystic fibrosis, Cilia dyskinesia syndromes, Immunodeficiency, Amyloidosis, Chronic fatigue syndrome) are the most common causes of NAR [6].

#### **4. Gustatuar rhinitis**

Typically, it starts after consuming hot or spicy food and alcohol. It starts with a food allergy or an unknown mechanism and continues with profuse rhinorrhea. Ipratropium bromide is used in the treatment [7].

#### **5. Occupational rhinitis**

Occupationally allergic and non-allergic can occur. There are four types. The first is an uncomfortable rhinitis without inflammation in the nose caused by smell. The second type is rhinitis that is caused by irritant and causes inflammation in the mucosa. The third type is corrosive rhinitis that occurs due to high concentration of chemicals in the nasal mucosa. Ammonia etc. occurs with inhalation of substances. The fourth type is rhinitis, which causes Ig E due to occupational exposure. Latex allergy in healthcare workers depends on this. Nasal saline irrigation solutions, nasal steroids and antihistamines are used in the treatment of this rhinitis [8] (**Table 1**).

#### **6. Hormonal rhinitis**

It is divided into two as gestational rhinitis induced by the menstrual cycle. Gestational rhinitis begins in the second trimester of pregnancy and continues until the second week of postpartum. It is related to pregnancy in another form of hormonal rhinitis. This can start in any week of pregnancy. Nasal saline irrigation is used in the treatment. In addition, they can benefit from the tapes used for the


#### **Table 1.**

*Drugs used in treatment [15].*

nose wings at night. The benefit of intranasal steroids in these patients has not been determined. The use of pseudoephedrine should be avoided during pregnancy, especially in the 1st trimester [9].

#### **7. Rhinitis medicamentosa (drug-induced rhinitis)**

It is a severe nasal congestion caused by the continuous use of agents such as oxymetazoline and phenylephrine, which are sympathomimetic agents. They use oral or topical steroids in treatment and sympathomimetic sprays are discontinued. Drugs such as ACE inhibitors, NSAIDs and Aspirin also have similar effects [10].

#### **8. Atrophic rhinitis**

Progressive nzal atrophy and Klebsiella ozaenae etc. It occurs due to mucosal colonization with microbial agents. There is a disturbing foul-smelling discharge on the jas. It can also develop after inferior turbinate surgery. Oral antibiotics, salty and oily washing solutions are used for malodorous discharge. Since the disease is very persistent, symptomatic patients should be followed up from time to time [11].

#### **9. Non-allergic rhinitis with eosinophilia syndrome (NARES)**

Known as non-allergic rhinitis with eosinophilic syndrome (NARES), the disease usually begins in adulthood; It is a type of non-allergic rhinitis characterized by negative skin test and normal IgE levels. Aspirin sensitivity, asthma and nasal polyps may develop in these patients. Eosinophilia is observed in patients. There is

also an increased risk of obstructive sleep apnea syndrome. Another variant is Non-Allergic rhinitis disease with eosinophilia in the blood called BENARES. Although the clinic of the disease is the same as NARES; In this disease, there is eosinophilia in the blood instead of nasal eosinophilia. Intranasal corticosteroids are sufficient in both NARES and BENARES [12].

### **10. Infectious rhinitis**

Infectious rhinitis is a type of rhinitis with acute or chronic runny nose, nasal congestion, frontal headache, smell disorders, post nasal discharge and cough. Most infectious rhinitis in children are viral and resolve with symptomatic treatment. If it is bacterial, antibiotics are used. In addition, nasal solutions, nasal steroids are also effective in treatment [13].

What are the risk factors?


#### **10.1 Complications**


#### **10.2 Diagnosis**

In non-allergic rhinitis, the diagnosis is made by exclusion. First of all, allergic rhinitis is ruled out. Sinus problems are then ruled out. So there are no definitive diagnostic criteria. To exclude, respectively.


#### **11. Treatment**

Non-allergic rhinitis treatment is similar to allergic rhinitis. In treatment;


Antihistamines are molecules that bind competitively to H1 receptors. They help us treat sneezing, runny nose and itchy nose by reducing the sensation of vascular permeability, smooth muscle contraction and itching.

Although first generation antihistamines are cheap, we know that there is serious central nervous system penetration. For this reason, unfortunately, almost 10–40% of the patients cause severe distraction, sleepiness and concentration impairment. Anti-cholinergic side effects such as dryness in mucosal membranes, urinary retention, constipation, tachycardia, and decreased visual acuity limit the use of these drugs in elderly patients. In addition, the antagonistic effects of these drugs, which require long-term use, related to serotonin receptors, unfortunately, can cause weight gain. Trefenadine and astemizole are the first 2nd generation antihistamines and their central nervous system penetration is less than the old generation; However, they were removed from use in clinical practice due to arrhythmia caused by susceptible patients. Loratadine and cetirizine are generally less sedating new generation drugs. Levocetirizine is an enantiomer of the cetirizine molecule and unfortunately causes sedation at the effective doses. Fexofenadine, terfenadine; deslarotadine are also active metabolites of loratadine; these are sometimes referred to as 3rd generation antihistamines. It is reported that fexofenadine does not cross the blood brain barrier and therefore does not sedate. However, unfortunately, this is not the case in clinical use. Desloratadine is also reported to have more sedation and anti-cholinergic side effects [15].

Recently, anti-inflammatory effects of antihistamines have been mentioned. It is stated that mast cells and basophils stabilize the receptor independently by inhibiting the transmembrane passage of calcium and intracellular cAMP, thus reducing

#### *Inflammation in the 21st Century*

the release of inflammatory mediators such as histamine, tryptase and prostaglandin. However, many antihistamines are unfortunately unable to stabilize these cells at therapeutic doses. Ketotifen, olopatadine, azelastine, bepotastine and alkaftadine are mostly known as both H1 receptor antagonists and dual-acting antihistamines with mast cell stability. It is stated that some antihistamines inhibit NF-B and GATA3 transcription via H1 receptor and thus achieve anti-inflammatory effect.

#### • Corticosteroids

Corticosteroids are the first-line anti-inflammatory drugs we know best for the treatment of many inflammatory diseases. Although corticosteroids have wellknown side effects, we see that they are still one of the most important pharmacological agents. In addition to growth retardation in children, side effects such as metabolism disorders, glaucoma and cataract formation, immunosuppression, suppression of the HPA axis, thinning of the skin, behavioral disorders and osteoporosis are the most common ones in all cases. Due to these restrictions arising in systemic use, it is mostly used intranasally in AR. Among the intranasal preparations, they are currently the most used pharmacological products in primary care. Although the anti-inflammatory mechanisms of corticosteroids are not very clear, the most important effects are seen as cytokine and chemokine inhibition. They bind to glucocorticoid receptors (GR) in the cytoplasm, dimerize and pass into the nucleus; they then associate with the glucocorticoid response element (GRE) and consequently increase the transcription of the gene codes of anti-inflammatory proteins such as lipocortin-1, IL-10, IL-1 receptor antagonist and neutral endopeptidase.

Glucocorticoids also cause a considerable reduction in the number of inflammatory cells in nasal lavage fluid. Especially, they cause a significant decrease in eosinophil numbers. This is due to their inhibitory functions on both IL-5 and GM-CSF. Currently, beclamethasone monohydrate, budesonide, flunisolide, triamcinolone acetonide, fluticasone (propionate and furoate), mometasone furoate, and ciclesonide are commercially available nasal topical corticosteroids. There are no significant differences in clinical efficacy between these preparations.

Local burning and stinging sensation, irritation, dryness and sometimes nosebleeds can be encountered as topical side effects with these preparations [15].

#### • Leukotriene antagocytes

Leukotrienes are inflammatory lipid mediators synthesized from arachidonic acid that can be produced by mast cells, eosinophils, basophils and macrophages. The adventure of arachidonic acid cleavage that started with the posfolipase A2 enzyme from the nuclear membrane continues with leukotriene synthesis. Arachidonic acid is metabolized to LTA4 via the 5-lipoxygenase (5-LO) enzyme. LTC4, LTD4 and LTE4 are then formed through different convertases. We call these leukotrienes "cysteinyl leukotrienes (CsyLTs)". CsyLTs has serious bronchial smooth muscle contraction, mucus production, edema and vascular permeability enhancing effects. LTD4 enhances the P-selectin pathway, increasing leukocyte adhesion and leukocyte aggregation to the inflammation site. It also plays an important role in eosinophil adhesion by increasing β2-integrins. As a result of nasal provocation with LD4 in normal humans, it was observed that nasal mucosal blood flow accelerated and airway resistance increased.

Leukotrienes can be physiologically antagonized by blocking their synthesis or receptors. Zileuton is a 5-LO synthesis inhibitor and it is a pharmacological product that can block nasal congestion in patients with AR after allergen provocation. For now, only montelukast, which is a Cys LT1 receptor antagonist, has been approved for AR and is a commercial product. Montelukast is observed to improve congestion during the day and at night, nasal discharge, nasal itching and sneezing, difficulty

#### *Non-Allergic Rhinitis DOI: http://dx.doi.org/10.5772/intechopen.94544*

falling asleep, and sleeping at night. It is thought to reduce the number of peripheral eosinophils and thus create an anti-inflammatory effect. However, despite all these, there are many publications showing that it is much less effective than intranasal corticosteroids in terms of these effects. Although it looks like a safe preparation in general; Some psychiatric side effects such as agitation, aggression, anxiety, hallucination, depression, insomnia, irritability, restlessness and suicidal thoughts are mentioned [15].

#### • Nasal decongestants

These drugs slow down nasal blood flow by antagonizing α1 and α2 adrenergic receptors in nasal capacitance vessel endothelium. In this way, they reduce nasal mucosal congestion and swelling. Better results can be obtained when combined with an antihistamine. Pseudoephedrine and phenylephrine, which are catecholamines, have oral forms. Although a runny nose can improve symptoms, it has no effect on itching, sneezing and eye symptoms in the nose. The imidazoline derivatives oxymetazoline, xylometazoline and naphazoline are suitable for intranasal use. Although they are fast intranasal decongestants and have fewer side effects, severe rebound congestion effects occur when the drug is discontinued. In some publications, it is mentioned that oxymetazoline inhibits T cells and cytokines such as IL-1β, TNF-α, IL-6 and IL-8. Some local nasal side related to these preparations.

#### **11.1 Monoclonal anti-IgE antibodies**

Omaluzimab is a humanized, recombinant, monoclonal antibody that blocks the binding of circulating IgE antibodies to the high affinity receptors in cells such as mast cells and basophil by complexing with the Ce3 region. There are many publications showing that patients with AR provide a very serious clinical benefit by significantly decreasing circulating IgE levels. In addition, it reduces FcR1 expressions on mast cells in both blood and tissue. It improves the nasal symptoms and increases the quality of life. It is an antibody that is well tolerated and has a very low risk of anaphylaxis (0.9/1000 applications). There are studies showing that SIT treatment applied together with omalizumab is more effective in single applications. The most important handicap is that it is currently an expensive treatment model [15].

#### **11.2 Capsaicin treatment, complementary and alternative medicine, surgery**

Capsaicin is bound to vanilloid resertors expressed in nasal C-fibers. It has been observed that repeated applications to the skin or intranasally cause desensitization in the peripheral nerve endings. It works well in vasomotor rhinitis in which neurotransmitters play an important role. It has been observed that it reduces symptoms such as nasal congestion, runny nose, and sneezing in AR. However, there are also publications showing that it has no clinical efficacy, especially in patients with house dust mite-sensitive PAR patients.

Nasal irrigation or irrigation with saline is a complementary treatment model in AR. In this form of treatment, it is ensured that the contact of the sinuses and pharynx with allergens and mucus is reduced. At the same time, edema in the nose is reduced. It has been shown that nasal saline application reduces the need for topical corticosteroids in children with AR.

It has been shown that exposure to microbes in children increases the expression of IL-10 and TGF-β inhibitory cytokines as well as the development of Th1-type immune response. There is evidence that beneficial microorganisms do this through toll-like respectors. Especially bifidobacteria and lactobacilli have such effects. There are studies showing that such probiotics can be effective in AR.

#### *Inflammation in the 21st Century*

There is no sufficient and scientific evidence that acupuncture is effective in AR.

It has been stated that UV-A and UV-B are used, and that the patients are not able to use drugs or get sufficient response in a few small series. In only one study on AR, infrared radiation therapy (FIR) has been tried. It has been stated that the application of the oven affects the thermo-receptors due to the heat it emits and can be effective by increasing the microcirculation.

Surgical intervention may be beneficial for sinusitis, nasal polyps, enlarged turbinates, or nasal septal deviation, if any, that do not respond to medical treatment [15].

### **Author details**

Erkan Yildiz Department of Otorhinolaryngology, Afyonkarahisar Şuhut State Hospital, Şuhut, Afyonkarahisar, Turkey

\*Address all correspondence to: dr.erkanyildiz@hotmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Settipane RA, Kaliner MA. Nonallergic Rhinitis. *American Journal of Rhinology & Allergy*. 2013;27(3\_suppl):S48-S51. doi:10.2500/ajra.2013.27.3927

[2] Eifan AO, Durham SR. Pathogenesis of rhinitis. *Clin Exp Allergy*. 2016;46(9): 1139-1151. doi:10.1111/cea.12780

[3] Sur DKC, Plesa ML. Chronic Nonallergic Rhinitis. *Am Fam Physician*. 2018;98(3):171-176.

[4] Ellis AK, Keith PK. Nonallergic rhinitis with eosinophilia syndrome and related disorders. *Clin Allergy Immunol*. 2007;19:87-100.

[5] Shahab R, Phillips DE, Jones AS. Prostaglandins, leukotrienes and perennial rhinitis. J Laryngol Otol. 2004 Jul;118(7):500-7. doi: 10.1258/0022215041615155. PMID: 15318955.

[6] Leader P, Geiger Z. Vasomotor Rhinitis. 2020 Aug 16. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. PMID: 31613484.

[7] Hellings PW, Klimek L, Cingi C, et al. Non-allergic rhinitis: Position paper of the European Academy of Allergy and Clinical Immunology. *Allergy*. 2017;72(11):1657-1665. doi:10.1111/ all.13200

[8] Shao Z, Bernstein JA. Occupational Rhinitis: Classification, Diagnosis, and Therapeutics. *Curr Allergy Asthma Rep*. 2019;19(12):54. Published 2019 Nov 27. doi:10.1007/ s11882-019-0892-0

[9] Wei J, Gerlich J, Genuneit J, et al. Hormonal factors and incident asthma and allergic rhinitis during puberty in girls. *Ann Allergy Asthma Immunol*. 2015;115(1):21-27.e2. doi:10.1016/j. anai.2015.04.019

[10] Zucker SM, Barton BM, McCoul ED. Management of Rhinitis Medicamentosa: A Systematic Review. *Otolaryngol Head Neck Surg*. 2019;160(3):429-438. doi:10.1177/0194599818807891

[11] Balur MB, Koçak HE, Altınay S, Özdamar K, Taşkın Ü, Oktay MF. Is submucosal fat injection effective in atrophic rhinitis? An experimental animal study. *Eur Arch Otorhinolaryngol*. 2017;274(10):3637-3642. doi:10.1007/ s00405-017-4670-0

[12] Becker S, Rasp J, Eder K, Berghaus A, Kramer MF, Gröger M. Non-allergic rhinitis with eosinophilia syndrome is not associated with local production of specific IgE in nasal mucosa. *Eur Arch Otorhinolaryngol*. 2016;273(6):1469-1475. doi:10.1007/s00405-015-3769-4

[13] Marti J, López F, Gascón I, Julve J. Propolis nasal spray effectively improves recovery from infectious acute rhinitis and common cold symptoms in children: a pilot study. *J Biol Regul Homeost Agents*. 2017;31(4):943-950.

[14] Lieberman PL, Smith P. Nonallergic Rhinitis: Treatment. *Immunol Allergy Clin North Am*. 2016;36(2):305-319. doi:10.1016/j.iac.2015.12.007

[15] Daramola OO, Kern RC. An update regarding the treatment of nonallergic rhinitis. *Curr Opin Otolaryngol Head Neck Surg*. 2016;24(1):10-14. doi:10.1097/MOO.0000000000000225

#### **Chapter 15**

## Islet Inflammation: The Link between Type 2 Diabetes and Pancreatic Cancer

*Alpana Mukhuty*

#### **Abstract**

The role of islet inflammation in type 2 diabetes (T2DM) and pancreatic ductal adenocarcinoma (PDAC) is complex. About 80% of pancreatic cancer patients have glucose intolerance or T2D. Chronic type 2 diabetes increases risk for pancreatic cancer, but the mechanisms are unknown. In this context two hypotheses exist: (i) pancreatic cancer causes diabetes and (ii) diabetes promotes the development of pancreatic cancer. Pancreatic ductal adenocarcinoma is the most common and deadly form of pancreatic cancer that is associated with diabetes. There are many possibilities by which obesity links to pancreatic cancer. These possibilities include insulin resistance, hyperinsulinemia and inflammation. Adipose tissue deposition near pancreas (peri-pancreatic depot) increase proinflammatory response to a high fat or high calorie containing diet. Inflammatory processes in the islets act as main mediators during the development and progression of pancreatic cancer. Recently, studies have been carried out to investigate the underlying mechanisms that contribute to tumorigenesis induced by inflammation. Tumor-elicited inflammation, secretion of pro-inflammatory cytokines and migration of immune cells play the key roles in initiation, promotion and progression of malignant metastasis in pancreatic cancer. Initiation and progression of islet inflammation in diabetes and pancreatic cancer occurs as a result of various protein–protein interactions and genetic events. The increase in pancreatic cancer cases may be attributed to the obesity endemic and obesity mediated Type 2 diabetes. The existence of link between islet inflammation in chronic diabetes and pancreatic cancer cannot be ignored, although the details about the underlying mechanisms are not clear, and must be studied in detail.

**Keywords:** Islet inflammation, type 2 diabetes, pancreatic cancer, obesity, insulin resistance

#### **1. Introduction**

Type 2 diabetes (T2D) is characterized by hyperglycemia which occurs due to impaired insulin production and reduced pancreatic beta cell population during insulin resistance. Most diabetes patients are able to compensate increasing insulin resistance by increasing insulin production. Now the decrease in insulin secretion occurs due to increased beta cell apoptosis, and the reason behind apoptosis remains endoplasmic reticulum stress, mitochondrial dysfunction and inflammation. Since a long time T2D and pancreatic cancer have been associated and

development of diabetes is related to occurrence of pancreatic cancer. The causes behind association of T2D with pancreatic cancer may be chronic inflammation and common progenitor cells for endocrine and exocrine pancreas, however still more research is needed in this field, and every detail about diabetes and pancreatic cancer must be studied [1].

Firstly, Type 2 diabetes is the third most possible risk factor for pancreatic cancer after obesity and cigarette smoking. Studies have shown that chronic type 2 diabetes increases risk of pancreatic cancer by 1.5- to 2.0-fold. Prediagnostic assessment of glucose and insulin levels may help in early diagnosis. The reasons behind development of diabetes-associated pancreatic cancer remain insulin resistance, hyperglycemia, hyperinsulinemia, and inflammation. On the other hand, people diagnosed with Type 2 diabetes may be part of a population of pancreatic cancer patients who have been detected earlier. There are several signaling pathways regulating metabolic processes which dictate cell proliferation and tumor growth. Better insight on the different mechanisms common in Type 2 diabetes and pancreatic cancer can be helpful in the development of new biomarkers and potent preventive or therapeutic strategies [1].

Ductal adenocarcinoma of pancreas is the fifth major cause of death in cancer in developed countries after lung, stomach, colorectal and breast cancer. 23% of the patients can live for 1 year after diagnosis and 6% of the patients have a 5-year survival rate due to advanced stage of cancer at the time of the diagnosis. Ductal adenocarcinoma of pancreas is also the thirteenth most common type of cancer and eight most common cause of cancer-related deaths. Here it must be mentioned that 80% of pancreatic cancer patients have been ailing with Type 2 diabetes or compromised glucose tolerance at the time of diagnosis [2–4].

Patients with ductal adenocarcinoma of pancreas and also Type 2 diabetes, have a record of diagnosis of diabetes less than 24 months before the diagnosis of ductal adenocarcinoma of pancreas in 74–88% of cases [5]. It means that Type 2 diabetes and ductal adenocarcinoma of pancreas show "dual causality," while chronic Type 2 diabetes remains a risk factor for the development of ductal adenocarcinoma of pancreas and, on the other hand, ductal adenocarcinoma of pancreas is also presumed to be a cause for Type 2 diabetes in many cases.

The Centre for Disease Control and Prevention recorded that ~29 million people in the U.S. suffered from Type 2 diabetes in 2014, while about 8 million of these patients have not yet been diagnosed. Also, ~86 million adults in the U.S. are known to be prediabetic, having a fasting plasma glucose level of 100–125 mg/dL, a 2-h plasma glucose level of 140–199 mg/dL, or a glycohemoglobin (HbA1c) level of 5.7–6.4% [6]. The global increase of ductal adenocarcinoma of pancreas further escalates the need to understand the pathophysiology of Type 2 diabetes. Chronic Type 2 diabetes is established to be a risk factor for ductal adenocarcinoma of pancreas [7]. Type 2 diabetes is also linked with obesity, and obesity also increases the risk for developing ductal adenocarcinoma of pancreas [8]. Type 2 diabetes is also associated with defective insulin function since insulin fails to suppress hepatic glucose release. As a result, peripheral glucose utilization mainly by skeletal muscle, is compromised, with initial increase in insulin levels since the beta cells try to overcome insulin resistance by producing more insulin [9]. With chronic Type 2 diabetes, beta cells undergo failure leading to apoptosis and decreased beta cell mass [10]. Patients with obesity and Type 2 diabetes are likely to suffer for long time periods with high intrapancreatic insulin levels due to beta cell compensation to overcome the increasing insulin demand and to maintain glucose homeostasis. Insulin is released into the circulation by beta cells through intrapancreatic portal circulation that also supplies blood to acinar and ductal cells near the islets. Acinar and ductal cells neighboring the islets may also get blood supply from intrapancreatic

#### *Islet Inflammation: The Link between Type 2 Diabetes and Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.98538*

portal circulation [11]. This close association allows high levels of islet hormones to directly get supplied to acinar and ductal cells, resulting in proxicrine effects on insulin receptors present on acinar cells and also on insulin like growth factor-I receptors in any differentiated cells in the region, enhancing survival and proliferation of the cells. Hence, intrapancreatic hyperinsulinemia, arising due to obesity and insulin resistance in prediabetic patients or in early diabetic patients contribute to increased risk in ductal adenocarcinoma of pancreas.

Compromised glycemic control is also associated with increased levels of advanced glycation end products (AGE) which activate RAGE, a receptor for AGE [12]. RAGE receptor belongs to the immunoglobulin super family and can bind to several ligands apart from AGE, including some proinflammatory cytokines that have role in inflammation and ductal adenocarcinoma of pancreas [12]. Also, activation of RAGE contributes to obesity and inflammation [13]. Excess of activation of RAGE also contribute to the higher prognosis of ductal adenocarcinoma of pancreas in Type 2 diabetes.

#### **2. Mechanisms between type 2 diabetes and pancreatic cancer**

The mechanism behind the association of Type 2 diabetes and pancreatic cancer is elaborate and include metabolic, hormonal, and immunological modifications that regulate tumor growth (**Figure 1**). The most presumed mechanisms behind the association between Type 2 diabetes and pancreatic cancer are insulin resistance, compensatory hyperinsulinemia and increased levels of circulating insulin-like growth factors (IGFs). In-vivo studies showed that islet cell turnover, linked with insulin resistance, is important for pancreatic cancer. Like, in hamsters, islet cell proliferation increase pancreatic ductal cancer [14], while destruction of islet cells by streptozotocin or alloxan impede pancreatic cancer prevalence [15, 16]. Also, biguanide metformin treatment inhibit the creation of pancreatic tumors by N-nitrosobis-(2-oxopropyl) amine, a potent pancreatic carcinogen. High-fat containing diet in hamsters normalize the islet cell turnover rate [17].

**Figure 1.** *Association between diabetes and pancreatic cancer [1].*

Pancreatic β-cells become hyperactive, their mass increase which together led to insulin over secretion to combat insulin resistance. The exocrine part of pancreatic tissue is exposed to much higher level of local insulin concentrations than the amount of insulin in the circulation of hyperinsulinemic patients. Insulin also acts as a growth-promoting hormone which increases cell proliferation. Hence, insulin not only promotes cell proliferation but also increases uptake of glucose [18], and both of these processes are important for development and progression of tumor. Moreover, insulin increases the availability of insulin like growth factors by decreasing hepatic production of binding proteins for insulin like growth factors [19, 20]. The two main properties of insulin like growth factor-1 (IGF-1) are mitogenic and antiapoptotic activities which increase growth of cells expressing insulin as well as IGF-1 receptor (IGF1R). Here it must be noted that IGF-1 and IGF1R are overexpressed in pancreatic cancer cells [21]. Also, IGF-1 regulated signal transduction elevates proliferation, invasion, and expression of different mediators of angiogenesis and decrease apoptosis of pancreatic cancer cells as well [22–24]. IGF1Rinduced signal transduction also activates several intracellular signal pathways, like Ras/Raf/mitogen-activated protein kinase and phosphoinositide-3 kinase/Akt/ mammalian target of rapamycin (mTOR) pathways [25]. Decreased levels of IGF binding protein 1 can predict increased risk of pancreatic cancer [26]. Unusual glucose metabolism can also predict presence of tumor cells, since most tumors have upregulated insulin-independent glucose uptake mechanisms while, diabetic animals with β-cell destruction induced by alloxan show reduced tumor growth [27]. This suggests that hyperglycemia has no role in increasing neoplastic growth in insulin deficiency. High dietary glycemic index increases the risk of pancreatic cancer due to deleterious effects of high postprandial glucose and increasing insulin demands [28]. Type 2 diabetes and diabetes associated obesity increase the risk of pancreatic cancer due to increased oxidative stress and inflammation during type 2 diabetes and also due to the link between oxidative stress and insulin resistance [29–32]. Antioxidant supplementation with vitamin E or α-lipoic acid can be preventive or curative in insulin resistance [33, 34]. Moreover, postprandial hyperglycemia directly increases oxidative stress leading to overproduction of superoxide by the mitochondrial electron-transport chain [35]. Impairment of the cellular redox state reduces tyrosine phosphorylation and elevates serine phosphorylation of insulin receptor substrate 1, which leads to impaired insulin-signaling pathway [35]. Moreover, obesity and macronutrient intake activate inflammatory signaling pathways [36, 37], and glucose and fat intake stimulate inflammation by increasing oxidative stress and the activating transcriptional factors such as nuclear factor-κB, activating protein-1 and early growth response-1 [38–40]. Also, adipose tissues may act as an endocrine organs to regulate the release of fatty acids, hormones, and cytokines like tumor necrosis factor-α, interleukin-6, and resistin [41].

Adipocytokines, which are secreted from adipocytes, are mainly involved in apoptosis, development, metabolism, innate immunity and inflammation. Proinflammatory cytokines are known to stimulate angiogenesis, tumor progression, and metastasis. During obesity or Typ2 2 diabetes altered levels or dysfunctions of many molecules like leptin [42], IGF-1 [43], and peroxisome proliferator-activated receptor-γ [44], lead to development of pancreatic cancer by impeding immune system.

Several genome-wide studies have shown new genetic variants that increase the risk of diabetes, and some of the susceptible loci already established in Type 2 diabetes are known to be involved in differentiation and development [45]. NR5A2 (or LRH1) is one such pancreatic cancer susceptibility gene identified in genome-wide association studies [46]. NR5A2 is a direct target of pancreatic duodenal homeobox (PDX-1) gene in pancreatic development and differentiation [47]. It regulates the

#### *Islet Inflammation: The Link between Type 2 Diabetes and Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.98538*

expression of developmental genes, like transcription factors hepatocyte nuclear factor (HNF)-3β, HNF-4α, and HNF-1β. On the other hand, NR5A2 expression is regulated by HNF-3β and HNF-1, so the case is regulated both ways. PDX-1 is necessary for pancreatic development and also for casual function of β-cell and secretion of insulin [48]. Mutations in HNF-1β gene is associated with maturityonset diabetes in the young people [49]. Better insight about the function of NR5A2 gene in the progression and development of pancreatic cancer can be helpful in curbing the risk of diabetes-linked pancreatic cancer and also decipher the genetic mechanisms behind Type 2 diabetes and pancreatic cancer.

#### **2.1 Genomic associations between type 2 diabetes, chronic pancreatitis and pancreatic ductal adenocarcinoma**

Several clinical and epidemiological studies associate the risk of ductal adenocarcinoma of pancreas to chronic Type 2 diabetes and chronic pancreatitis (CP). The genetic reasons of susceptibility among all these three diseases are quite variant however, some reasons are common. The mechanism behind the function of these genes and how they influence susceptibility is not common because of the difference in methodology of identification of the genes. Interestingly, all three diseases share these characteristics: 1) all patients have a report of family history or familial clustering, which indicate shared genetic or environmental influence, 2) difference in age of patients at the time diagnosis is due to familial risk, and 3) analyzing Mendelian segregation prove that in some families there are some hereditary components which demonstrate the common features of the gene [11]. Apart from genetics factors, there are epidemiological factors like obesity in diabetes, alcohol intake in chronic pancreatitis, and smoking in ductal adenocarcinoma of pancreas that may work with genetic factors to increase the risk. Several approaches have been evolved to discover these susceptibility genes, from family-based case control studies and cohort studies, from where a list of candidate genes is identified, and large-scale genome-wide association studies (GWAS) are conducted to search for single nucleotide polymorphisms (SNPs) or next-generation sequencing. The genetic basis of Type 2 diabetes is characterized as polygenic, having implication of over 50 genes [50]. Any single major gene cannot explain the genetic risk of Type 2 diabetes except in some rare cases [51]. However, chronic pancreatitis and ductal adenocarcinoma of pancreas can be explained by mutations in some major genes. Genome-wide association studies (GWAS) have identified many low-penetrance common SNPs which are associated with risk of ductal adenocarcinoma of pancreas. Among all these three diseases, Type 2 diabetes has been studied in detail, which depict that Type 2 diabetes is a multifactorial disease and is genetically complex. Variants of more than 50 genes have been studied which increase genetic risk. These genes are divided into some having modest effect like PPARG and KDNJ11, and others having strong association like TCF7L2, WFS1, HDF1B, FTO, CDKN2A, and SLC20A8. New strategies have been developed which have characterized the genetic basis of the disease through subclinical or related phenotypes by predisposition of the genes [52]. Since Type 2 diabetes is a polygenic risk model, each genetic variant has a small effect. These genetic variants improve risk assessment from common risk factors like age, sex, family history and BMI (Body Mass Index) [53]. Family-based studies and data on pathophysiology of chronic pancreatitis facilitate success in explaining the genetic heterogeneity [54]. Most of the variations in susceptibility are due to acute and chronic pancreatitis being related to genetic variations among patients. Alcohol was considered to be the primary reason behind genetic contributions but after the discovery of PRSS1, CFTR, and SPINK1 variants which associated with pancreatitis the reasons have been resolved [55]. Hence, no

single factor can cause pancreatitis, and majority of cases having acute and chronic pancreatitis have multiple variants of a gene, or multiple genes having epistatic interactions, or genetic factors coupled with environmental cues.

The genetic predisposition to ductal adenocarcinoma of pancreas is difficult due to the poor collection and analysis of biospecimens from patients owing to their low survival rate. Alike Type 2 diabetes and chronic pancreatitis, ductal adenocarcinoma of pancreas is also genetically heterogeneous. The identification of susceptibility genes has led to discovery of some rare gene mutations which are associated with cancer syndromes linked with common single nucleotide polymorphisms (SNPs). Study designs on family hierarchy and case-controls have led to discovery of mutations in known syndrome-associated genes, like BRCA1, BRCA2, CDKN2A, and CFTR. Moreover, next-generation sequencing has led to identification of additional mutations like PALB2 [56] and ATM [57]. Patients with sporadic ductal adenocarcinoma of pancreas carry germline mutations in major genes [58] and it changes the present knowledge for risk assessment. Large numbers of sporadic cases of ductal adenocarcinoma of pancreas and healthy subjects have exposed SNPs in chromosomal regions containing ABO, TERT, and CLPTM1L and other genes. Nevertheless, risk modeling using GWAS SNPs cannot provide sufficient genetic information that can improve prediction of pancreatic cancer [59].

#### **2.2 Role of obesity and pancreatitis mediated inflammation in pancreatic ductal adenocarcinoma**

Obesity is linked with an elevated risk of cancer, including pancreatic cancer [60]. The observed increase in pancreatic cancer epidemiology and deaths can be partially attributed to obesity taking the form of an endemic disease. Obesity can lead to pancreatic cancer, insulin resistance, hyperinsulinemia and inflammation by many possible ways [61]. Pancreatic cancer development can be attenuated in genetically engineered mouse model by using nonsteroidal anti-inflammatory drugs, which indicate that tissue inflammation plays an important role in this disease [62]. Tissue inflammation during obesity creates a perfect microenvironment for tumor initiation and promotion. Besides obesity, increase in BMI and visceral adiposity bears a strong link with metabolic diseases and gastrointestinal cancers, together with pancreatic cancer [63]. The accumulation of adipose tissue near the pancreas (peri-pancreatic depot) lead to an enhanced proinflammatory reaction in response to high-fat or high-calorie containing diet compared to peri-gonadal depot [64]. The association between adipose tissue depot-specific reactions to dietinduced obesity and the effect of these adipose tissue depots on cancer development is very crucial to understand the connection between body condition and risk of cancer. Moreover, high-fat or high-calorie containing diet increases the progression of pancreatic intraepithelial neoplasia, which is a known precursor of ductal adenocarcinoma of pancreas, and this accelerates the incidence of pancreatic cancer in an invasive and metastatic manner in conditional KrasG12D mouse model [65, 66].

#### **2.3 Mechanisms behind type 2 diabetes in pancreatic ductal adenocarcinoma**

To be specific, prevalence of Type 2 diabetes among ductal adenocarcinoma of pancreas patients is really very high. Type 2 diabetes is found in 47% of ductal adenocarcinoma of pancreas patients compared with only 7% of healthy subjects, and a normal fasting glucose occurs in 59% of healthy subjects, while it is found only in 14% of ductal adenocarcinoma of pancreas patients [5] (**Figure 2**). In 74% of ductal adenocarcinoma of pancreas patients with diabetes, diabetes is diagnosed within 24 months before the diagnosis of ductal adenocarcinoma of pancreas [67].

*Islet Inflammation: The Link between Type 2 Diabetes and Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.98538*

**Figure 2.** *Prevalence of type 2 diabetes in ductal pancreatic adenocarcinoma [5, 11].*

This remarks that in most of the patients, new-onset diabetes is due to the tumor and this diagnosis of diabetes may be a useful "biomarker" for the diagnosis of ductal adenocarcinoma of pancreas. Although known risk factors for Type 2 diabetes like obesity, age and family history of diabetes are also the common risk factors in case of risk factors for ductal adenocarcinoma of pancreas, the occurrence of Type 2 diabetes in ductal adenocarcinoma of pancreas is pretty higher than the occurrence of Type 2 diabetes among all other common types of cancer. Type 2 diabetes is found in 68% of patients with ductal adenocarcinoma of pancreas while it occurs in 14.8–23.5% of patients with breast, colon, lung, and prostate cancers [68]. Also, insulin resistance is common in patients with both ductal adenocarcinoma of

pancreas and Type 2 diabetes, while many patients with ductal adenocarcinoma of pancreas undergo weight loss. Deteriorating glycemic control along with weight loss occurs in ductal adenocarcinoma of pancreas along with its incidence in Type 2 diabetes. These common characteristics give alert to the clinicians for the possibility of ductal adenocarcinoma of pancreas -associated diabetes. New-onset diabetes associated with ductal adenocarcinoma of pancreas can be cured after tumor resection, if there are enough islets left in the pancreatic tissue. Several reports show that Type 2 diabetes improves after resection of pancreatic tumors [69]. 57% of the patients with new-onset diabetes get cured of diabetes post operation of pancreatic tumors, while all of ductal adenocarcinoma of pancreas patients with long-standing diabetes cannot be cured of diabetes even after pancreatic resection [5] (**Figure 3**). These data strongly support that new-onset diabetes is associated with ductal adenocarcinoma of pancreas and it can be a paraneoplastic phenomenon, where malignancy interferes with insulin secretion or insulin function, finally leading to Type 2 diabetes. Numerous studies have tried to identify the mechanisms behind Type 2 diabetes caused by ductal adenocarcinoma of pancreas or the genomic and protein markers of Type 2 diabetes caused by ductal adenocarcinoma of pancreas. Connexin 26, a gap junction protein, is highly overexpressed in islets of ductal adenocarcinoma of pancreas patients with Type 2 diabetes [70], and a pancreatic ductal adenocarcinoma -derived S-100A8 N-terminal peptide is a diabetogenic agent [71, 72] which is also upregulated patients with ductal adenocarcinoma of pancreas associated with new-onset diabetes. Vanin-1 and matrix metalloproteinase 9 can also act as predictors of ductal adenocarcinoma of pancreas associated diabetes [73]. Vanin-1, is also overexpressed during inflammation, which means that mediators of inflammation play an important role in damaged islet function and insulin function in ductal adenocarcinoma of pancreas. Pancreatic Polypeptide (PP) release increases in Type 2 diabetes, and a deficit in PP response due to nutrient ingestion can transform into new-onset diabetes caused by pancreatic exocrine

disease. Basal and meal-stimulated PP release significantly decreases in patients with diabetes associated with ductal adenocarcinoma of pancreas localized in the head of pancreas in comparison to patients with Type 2 diabetes [11].

#### **2.4 Significance of type 2 diabetes in pancreatic ductal adenocarcinoma**

Some researchers say that diabetes does not contribute to earlier diagnosis or clinical features or tumor size or prognosis of pancreatic cancer [74], although, previous studies had established that diabetes can predict pancreatic cancer [75]. A study compared diabetic and non-diabetic patients and observed a worse overall mortality and median survival in diabetic patients [76]. In another study, patients with diabetes had a better overall survival [77]. On the other hand, Type 2 diabetes is known to confer a poor survival in ductal adenocarcinoma of pancreas patients [78]. Actually, gender and mean age of the patients in these two studies regulated the number of comorbidities, time of diabetes and also time for development of complications in diabetes [75]. Use of preventive medicine, frequent clinical followup and earlier diagnosis of ductal pancreatic adenocarcinoma can generate a better median survival.

#### **3. Future perspectives of dealing with pancreatic ductal adenocarcinoma**

The explanation of hormonal [79], paracrine [21] and autocrine [22, 23] mediators of pancreatic cancer and its association with new-onset diabetes can be helpful in pathogenesis and showing new therapeutic targets. A better explanation of the epidemiology of pancreatic cancer, is poorly controlled diabetes or it can be an intrinsically genetic [8] or epigenetic [80–82] or immunologic [83, 84] or gastrointestinal microbiota [85, 86] or tissue microenvironment which are characteristic of Type 2 diabetes [87–89] patients progressing towards pancreatic cancer.

The various techniques like gene sequencing, lymphocyte flow cytometry, mRNA profiling, PCR studies and microbe identification microarray from Type 2 diabetes patients in different stages of progression can help in early diagnosis and prevent diabetic complications in pancreatic cancer and diabetes. Molecular biomarkers can be very crucial to diagnose patients with new-onset diabetes who should be tested with endoscopic ultrasound for identifying pancreatic cancer [75]. Hyperinsulinemia can negatively predict value development of new-onset diabetes associated with pancreatic cancer if all other hormonal, paracrine or autocrine factors play against development of insulin resistance [75].

Metformin, a well-known medication for Type 2 diabetes, improves survival in pancreatic cancer patients and has prognostic effects [90]. The knowledge available on the mechanism of action of metformin helps in the understanding of the ductal adenocarcinoma of the pancreas cancer pathways [75].

#### **4. Altered intracellular metabolism in pancreatic ductal adenocarcinoma**

Deregulated systemic physiology is the effect of disruption of energy homeostasis, and metabolic processes within the cells of a pancreatic tumor can also be knowledgeable [91]. Malignant cells of a pancreatic tumor, have alterations that are mediated by both oncogene-driven programs and also by the rare physiology of tumor. Pancreatic tumors have a dense, fibrotic stroma which inhibits vascular function and also disrupts delivery of nutrients and oxygen [92]. Mutant Kras

expression regulates metabolic networks facilitating redox balance, bioenergetics, and anabolic metabolism for better survival and cell proliferation under these poor circumstances [93–95]. Nutrients recycled by autophagy fuel these pathways [96, 97] and also the nutrients scavenged by nonspecific bulk extracellular space engulfment or by micropinocytosis [98] as well as overexpressed nutrient importers help in regulating these pathways [93, 99]. Together, the regulation of metabolism of pancreatic cancer cells are controlled by oncogene-driven pathways, and they engage nutrient scavenging mechanisms as well as improve nutrient utilization to overcome the problems of insufficient vascularization [91].

Malignant cells constitute 10% of the total cellular content of a pancreatic tumor [92]. As a result, the non-malignant cells help in shaping the metabolic condition and facilitate tumor growth [91]. These processes can be divided into 2 types: First, the cooperative reactions between non-malignant cells and malignant cells support the metabolism in cancer cells, and second, the reaction between malignant and non-malignant cells is competitive and it happens between tumor cells and the antitumor immune reaction [100].

One main cooperative reaction is the nutrient exchange pathway that occurs between pancreatic cancer cells and activated pancreatic stellate cells (PSCs) [101]. Pancreatic cancer cells are known to induce autophagy in the PSCs. As a result, protein breakdown occurs through autophagy and nonessential amino acids are released. Now, the pancreatic cancer cells engulf alanine and utilize it to in mitochondrial metabolism and also in the biosynthesis of cellular building blocks. Here it must be mentioned that alanine can be used in metabolism in replacement of glucose and glutamine, and the biosynthetic substrates also aid in cancer cell metabolism. If this metabolic crosstalk pathway is blocked or inhibited by suppressing autophagy particularly in the PSCs then it can lead to a dramatic decrease in tumor growth. Interestingly, pancreatic tumors can suppress immune responses and are highly resistant to immunotherapies [102]. Local nutrient depletion and waste accumulation indeed play important roles in aiding tumor immune suppression [100]. Moreover, Cytotoxic T-cells, are intrinsically less apt at obtaining nutrients than oncogene-driven cells, and they are compelled to compete for the limited nutrients like carbohydrates and amino acids, in a tumor microenvironment, and later result in defective antitumor immune response. The compromised antitumor T-cell response in melanoma and sarcoma is directly connected with glucose deprivation [103, 104], while high titres of lactate aid in the polarization of antiinflammatory macrophages [105]. Mutant Kras-expressing pancreatic cancer cells vigorously consume glucose and then release lactate (so-called, Warburg metabolism) [93], and all of these mechanisms result in suppressed immune function in pancreatic cancer. Moreover, M2 type anti-inflammatory macrophages and cancer cells can exhaust tumors of amino acids such as arginine and tryptophan [106]. These processes also restrict antitumor T-cell responses and aids the differentiation of T-cells into anti-inflammatory T-regulatory cells.

#### **5. Role of bariatric surgery in obesity and pancreatic ductal adenocarcinoma**

Premorbid obesity unpleasantly influences ductal adenocarcinoma of pancreas associated mortality in a dose-dependent manner [107, 108]. A high BMI is also linked with an increased risk of ductal adenocarcinoma of pancreas [107, 108]. The etiology of obesity-linked diseases starts with excess energy and deposition of triglyceride in the adipose tissue. This excess of triglyceride cannot be completely deposited in the adipose tissue, hence ectopic fat deposition occurs in various

*Islet Inflammation: The Link between Type 2 Diabetes and Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.98538*

organs like liver and pancreas. Triglyceride deposition in the liver leads to oxidative stress and inflammation, resulting in cirrhosis, steatohepatitis and hepatocellular carcinoma. Similar mechanisms occur in the pancreas. Free fatty acids and inflammatory mediators remain in high amounts in the pancreas of obese high fat fed mice [109], and this accelerates tumor growth [110]. Fat depots in liver and pancreas increase in obese individuals. After bariatric surgery, weight loss occurs, and hepatic and pancreatic fats rapidly disappear [111]. After weight loss, insulin resistance and circulatory levels of inflammatory factors also rapidly normalize [112]. Weight loss occurring after bariatric surgery decreases cancer mortality by 40–60% [113, 114]. Also, the risk of ductal adenocarcinoma of pancreas is significantly lower among the patients who have undergone bariatric surgery [115]. Nevertheless, bariatric surgery is restricted to individuals with high obesity (mean BMI >40 kg/m2). Substantial weight loss (mean > 30% total body weight) occurs in these individuals after bariatric surgery. Moreover, intentional weight loss by bariatric surgery or changes in lifestyle or pharmacotherapy or less invasive surgical or endoscopic procedures also helps in reducing the risk of cancer in obese patients [115].

#### **6. Role of visceral and Peripancreatic fat in pancreatic ductal adenocarcinoma**

BMI is a well-known marker for adiposity, and can also be linked with insulin resistance, metabolic syndrome and gastrointestinal malignancies, like ductal adenocarcinoma of pancreas [116]. Highly inflamed visceral adipose tissue (VAT) in obese patients remains the main reason behind metabolic dysfunction and gastrointestinal cancer due to the close proximity of the visceral organs with the portal system. VAT has a high correlation with occurrence of ductal adenocarcinoma of pancreas. Interestingly, conditional KRasG12D (KC) mice fed high-fat and high calorie containing diet gained more weight than the standard diet fed mice and ended up developing hyperinsulinemia and hyperleptinemia with extensive VAT expansion and high inflammation [64, 65, 117]. These obese KC mice had highly inflamed pancreas and were more prone to develop ductal adenocarcinoma of pancreas than the control mice fed on standard diet and this occurred in the male mice, which meant that the sex hormones had a role in it [117]. Interestingly, the increased incidence of pancreatic ductal adenocarcinoma in obese KC mice was largely seen in male mice, suggesting a role for sex hormones in this process, since the female mice gained more adipose tissue subcutaneously [64, 65, 117].

#### **7. Role of gut microbiome in pancreatic ductal adenocarcinoma**

Human microbiome has gained a lot of popularity recently to tackle prevention, as well as early diagnosis, and treatment of ductal adenocarcinoma of pancreas, since many diseases have now started to be linked with composition of microbiome [118–120]. The composition of microbiome also interferes with development of ductal adenocarcinoma of pancreas and its relation with diabetes, obesity, and inflammation [121]. Ductal adenocarcinoma of pancreas is an inflammation-mediated cancer and gut microbiome can stimulate chronic inflammation via changes in molecular pattern recognition receptors. These pattern recognition receptors and their downstream signaling cascade leads to the incidence of inflammationmediated cancers. These bacteria regulate the efficiency of calorie absorption in the intestines and hence lead to obesity. Many diseases like Type 2 diabetes, obesity, and chronic pancreatitis are linked with chronic inflammation, which also result in

ductal adenocarcinoma of pancreas [122]. Moreover, alteration of oral microbiome increases risk of ductal adenocarcinoma of pancreas, and it can be a useful biomarker of the disease. Specific abundance in certain oral bacteria and gut microbiome in pancreatic secretions or fecal matter may be associated with risk of ductal adenocarcinoma of pancreas, hence these knowledges can help in preventing or in early diagnosis of ductal adenocarcinoma of pancreas [122].

#### **8. Role of inflammation in pancreatic ductal adenocarcinoma**

As already mentioned above, chronic inflammation in pancreas or chronic pancreatitis is a major reason behind ductal adenocarcinoma of pancreas. Activated PSCs play a key role in progression of chronic pancreatitis. Activation of PSCs is also increased by cytokines secreted from injured acinar and immune cells. The mechanisms underlying triggering of macrophages and survive the fibrotic processes by reacting with PSCs, if interfered end in suppression of inflammation and fibrosis in chronic pancreatitis [123]. Alcohol and smoking are also potent risk factors for chronic pancreatitis and ductal adenocarcinoma of pancreas. IL-22 signaling during inflammation and cross talk between immune cells and PSCs is one of the signaling involved in smoking-induced progression of chronic pancreatitis [124]. The other pathways that are behind progression of ductal adenocarcinoma of pancreas are IL-6 and histone deacetylases in immune and cancer cell interactions, which together mean that immune signals are key factors in promoting pancreatitis and pancreatic cancer progression [125]. However, most cases of ductal adenocarcinoma of pancreas are resistant to immunotherapies treatment with immune checkpoint antibodies because inflammatory processes are important in promoting the malignant transformation, growth, and metastasis of pancreatic cancer. For example, Kras mutations stimulate profuse cytokine and chemokine secretion in tumor epithelial cells and recruit immune cells like macrophages, dendritic cells (DCs), and myeloid-derived suppressive cells, all of which stimulate tumor growth and progression. So, all these cells need to be reprogrammed in ductal adenocarcinoma of pancreas to create a favorable immunostimulatory environment for efficient immunotherapy. Since, ductal adenocarcinoma of pancreas is often followed by metastatic relapse even after complete surgical pancreatic resection, the newly developed cancer cells fail in immunotherapy, which means that a better knowledge about the factors affecting metastasis is important for the development of more effective immunotherapies and treatments [126]. Early metastases are linked with dense networks of CD11b + CD11c + MHC-II + CD24 + CD64 and low F4/80 cells, and all of these cells develop from monocytes and aid in promoting metastasis by increasing regulatory T-cells and suppressing the development of cytotoxic T-cells. Phenotypically similar dendritic cells are seen to accumulate at primary and secondary sites in pancreatic portions of ductal adenocarcinoma of pancreas patients [127]. Dendritic cells can be reprogrammed into immunostimulatory antigen-presenting cells in tumor metastasis, which is one of the most popular immunotherapeutic strategies at present. Another strategy is based on the availability of tumor-binding immunoglobulin G antibodies along with some dendritic cell-stimulating molecules which help the enable tumor-associated dendritic cells to uptake, process, and present a variety of tumor antigens to T-cells. Then the T-cells proliferate and attack the tumors throughout the host. This technique can eradicate metastases, and also primary tumors in many types of cancers, including ductal adenocarcinoma of pancreas by overcoming tumor-mediated immunosuppression [128]. But the tumor cells tend to enter into the circulation and metastasize and end up colonizing distant organs [129]. Metastatic ductal adenocarcinoma of

*Islet Inflammation: The Link between Type 2 Diabetes and Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.98538*

pancreas has many epigenetic modifications in the primary tumor. While the cancer cells circulate in clusters and colonize different organs, the establishment of a new premetastatic niche in a new organ includes proinflammatory processes, exosomes and immune cells [130]. All of this information can help in developing new therapeutic approaches targeting different agents for primary ductal adenocarcinoma of pancreas and also in its metastasis.

#### **9. Conclusion**

Ductal adenocarcinoma of pancreas is a very challenging malignancy with a high incidence and high lethality. Moreover, the disease has intricate relationships with diabetes and obesity. Type 2 diabetes has its own risks and can be both a risk factor for ductal adenocarcinoma of pancreas as well as an early manifestation of the disease. Obesity is also strongly associated with increasing risk of ductal adenocarcinoma of pancreas. However, every detail about all these diseases and their association is not fully understood, particularly the specific mechanisms that contribute to ductal adenocarcinoma of pancreas are not clear, which makes the diagnosis and treatment of ductal adenocarcinoma of pancreas very difficult. Hence present research is targeted in bringing out all the minute details and the mechanisms to tame this malignancy and preferably find a cure or a preventive mechanism or at least a better biomarker in near future.

#### **Acknowledgements**

AM is thankful to the Science & Engineering Research Board (SERB), Department of Science & Technology, Govt. of India, for her JRF fellowship (Grant No. ECR/2017/001028/LS). The author is thankful to Dr. Rakesh Kundu, Chandrani Fouzder, Snehasis Das and Dipanjan Chattopadhyay for technical assistance and constant encouragement.

#### **Conflict of interest**

The author declares no conflict of interest.

#### **Notes/thanks/other declarations**

The author thanks to the Head of the Department of Zoology, for providing the assistance in the research work.

*Inflammation in the 21st Century*

#### **Author details**

Alpana Mukhuty Cell Signaling Laboratory, Department of Zoology, Visva-Bharati University, Santiniketan, India

\*Address all correspondence to: alpanamukhuty@yahoo.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Islet Inflammation: The Link between Type 2 Diabetes and Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.98538*

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#### **Chapter 16**

## Hypomelanosis Secondary to Cutaneous Inflammation

*Behzad Dalvand*

#### **Abstract**

Hypomelanosis is a prevalent skin disorder in individuals with dark skin. Numerous inflammatory skin disorders cause hypomelanosis, even depigmentation. Its pathogenesis remains unknown, but it can be attributed to changes in melanin production in response to inflammation. The clinical manifestations, often including lesions with ill-defined borders limited to the site of inflammation, mostly appear in individuals with dark skin. The most important way to manage PIH is to effectively treat the underlying skin disorder that has led to it, however, medical therapy and phototherapy can be helpful, as well.

**Keywords:** PIH, hypomelanosis secondary to inflammation, depigmentation, pathogenesis, melanocytes

#### **1. Introduction**

Hypomelanosis is a prevalent skin disorder in dark-skinned Individuals. The numerous skin diseases that cause hypomelanosis include psoriasis, mycosis fungoides, sarcoidosis, pityriasis lichenoides chronica, lichen striatus, lupus erythematosus and lichen sclerosus. Different clinical pictures of lesions and multiple factors in developing post-inflammatory hypopigmentation (PIH) constitute a diagnostic challenge for dermatologists.

#### **1.1 Pathogenesis**

Although many studies have addressed PIH, its exact etiology remains unknown and needs the assistance of cytologists. PIH is actually caused by a disorder in melanocyte-keratinocyte interactions. The release of inflammatory agents can be involved in the synthesis of melanin or transfer of melanin to keratinocytes, especially by inhibiting the transfer of melanin from melanocytes to keratinocytes. Melanocytes can respond by changing melanin production in response to posttraumatic stress and inflammation.

Individuals inherit chromatic tendency in the predominantly autosomal dominant form. Hypopigmentation can develop as a result of damage to melanocytes, especially in patients with weak melanocytes. It is worth noting that melanocytes can be weak even in individuals with fair skin. Different factors control melanogenesis as a complex process that involves the synthesis, transfer and release of melanin. PIH is mostly caused by the inhibition rather than destruction of melanocytes. Moreover, severe inflammatory responses of the skin can cause melanocyte loss or death and thus pigmentation changes.

#### **1.2 Clinical manifestations**

The clinical manifestations, often including lesions with ill-defined borders limited to the site of inflammation, mostly emerge in individuals with dark skin, especially in those prone to hypopigmentation or even depigmentation. They are associated with diagnostic challenges, especially in children, as they can be associated with minor or asymptomatic variations.

The clinical features normally vary based on the primary skin lesions and the lesion margins are often blurred.

The rate of hypopigmentation varies with the age and severity of the cutaneous lesions and severity of the inflammation. Identifying the underlying cause of hypopigmentation can be difficult upon the patient admission, as inflammation of advanced lesions may decrease in severity or even gradually disappear (**Figure 1**). A complex description and frequent examinations are therefore required in these cases. Biopsy and histological examinations are also required in the absence of inflammatory symptoms.

#### **1.3 Treatment**

The most important treatment is to effectively treat the underlying skin disorder that has led to PIH because PIH usually improves over time.

UVB phototherapy and epidermal melanocyte transplantation can help treat completely-destroyed or depigmented melanocytes. Photo protection, apply broad spectrum (UVAUVB) SPF 30 or 50 and reapply every 2–4 hours selftanner (dihydroxyocetonc). Applying topical ironoxide (3%) can effectively protect the skin against blue visible light, especially in dark-skinned patients with PIH.

**Figure 1.** *Psoriasis, showing multiple-well dermarcated hypopigmented lesions.*

### **2. Diseases of PIH**

#### **2.1 Pityriasis alba**

#### *2.1.1 Introduction*

Pityriasis albais a prevalent benign but chronic and inflammatory dermatosis and a minor skin feature of atopic dermatitis that mostly emerges in 3 to 16-year-old individuals. Its prevalence is 1.9%–9.9% in children and up to 5%, especially when coupled with atopic dermatitis.

#### *2.1.2 Pathogenesis*

Different mechanisms can be considered for explaining the still-unknown etiology of pityriasis alba. A history of atopic dermatitis constitutes a pathogenic factor in pityriasis alba.

A Positive Relationship between health habits and pityriasis alba, frequent bathing and excessive washing may contribute to the lesion.

Nutritional factors and copper deficiency are also effective. Tyrosine in dermal cells involved in producing melanin is activated by copper. Pathological examinations with electron microscopy and light microscopy showed decreases in the number and size of melanosomes in the affected skin [1].

#### *2.1.3 Clinical manifestations*

The eruptions usually appear as round or oval macules or patches with an indistinct border with or without slight and often asymptomatic scales (**Figure 2**). The lesions normally become more visible in summer and may initially appear pink in

#### **Figure 2.**

*Pityriasis alba: A common disfiguring hypomelanosis, which, as the name indicates, is a white area (alba) with very mild scaling (pityriasis). It is observed in a large number of children in the summer intemperate climates.*

#### *Inflammation in the 21st Century*

a way that the erythema subsides and turns white with powdery appearance and a pink border within a few weeks. With a size of 5–30 mm, the lesions mostly involve the face. Direct examination of scrapings with 10% KOH and slit-skin smear are respectively used to diagnose tinea versicolor and leprosy, and Wood's lamp examinations are performed for distinguishing vitiligo and the diseases associated with hypopigmentation.

It is mostly a cosmetic problem in persons with brown or black skin and commonly occurs on the face, as in this child. Among 200 patients with pityriasis alba, 90% ranged from 6–12 years of age. In young adults, PA quite often occurs on the arms and trunk [2].

#### *2.1.4 Treatment*

If pityriasis alba is left untreated, it can turn chronic and recurrent, although it self-heals in most cases after puberty. Topical steroids class V help reduce the lesion inflammation caused by pityriasis alba. Calcineurin inhibitors such as pimecrolimus cream1% and tacrolimus ointment 0.3% or 0.1% with anti-inflammatory properties can positively affect and activate tyrosinase and thus increase melanin synthesis [3]. Narrow-band UVB and excimer light or excimer laser treatment also yields proper responses through 5–10 treatments of 308 nm excimer laser.

#### **2.2 Cutaneous lupus erythematosus**

#### *2.2.1 Introduction*

Cutaneous lupus erythematosus is more prevalent in women with dark skin, especially in their fourth decade of life. One to five percent of the patients may progress to systemic lupus erythematosus.

#### *2.2.2 Pathogenesis*

Trauma and UVR may have been involved in the onset and exacerbation of symptoms in a person with a predisposed background. Photosensitivity is also observed in 50% of the patients. Histologic examinations can suggest lymphocytic interface dermatitis with basal layer degeneration (hydropic degeneration), keratinocyte apoptosis, basement membrane thickening (greatest in discoid lupus erythematosus), perivascular and periadnexal lymphohistiocytic infiltrate, follicular plugging, cutaneous mucinosis, epidermal atrophy, fibrosis, hypomelanosis and amelanosis, which are observed especially in the center of the lesions.

#### *2.2.3 Clinical manifestations*

As the most prevalent manifestations, sharply demarcated lesions in discoid lupus erythematosus (DLE) can be round, justifying the term "discoid". The face and scalp constitute the most commonly affected sites.

DLE lesions are usually asymmetric and asymptomatic with a well-defined and elevated margin, which explains their red to violaceous color. These lesions often appear atrophic and hypopigmented or depigmented, especially in black individuals with prominent follicular plugs (**Figure 3**). Their hypopigmented center is often surrounded by a hyperpigmented margin.

Systemic lupus erythematosus can be assessed by performing a complete blood count, an erythrocyte sedimentation rate and an antinuclear antibody test.

*Hypomelanosis Secondary to Cutaneous Inflammation DOI: http://dx.doi.org/10.5772/intechopen.96256*

#### **Figure 3.**

*Discoid lupus erythematosus; there are well-defined, erythematous, scaling lesions with a pigmented margin and central depigmention and behind the ear in this west Indian.*

#### *2.2.4 Treatment*

Initial treatment options include topical steroids, intralesional steroids, antimalarial medications such as Hydroxychloroquine, and acitretin. High-potency corticosteroids are recommended for the facial lesions.

Intralesional triamcinolone, commonly at a concentration of 4 to 5 mg/ml, can be very effective especially in active discoid lesions.

Reports suggest the successful application of new topical immunomodulators such as tacrolimus to cutaneous lesions.

#### **2.3 Systemic sclerosis (scleroderma)**

#### *2.3.1 Introduction*

As a collagen vascular disease with cutaneous fibrosis as its skin manifestation, systemic sclerosis causes skin tightening and pigmentary changes. The incidence and prevalence of scleroderma are respectively below two per million and 25 per million [4, 5].

#### *2.3.2 Pathogenesis*

Abnormal immune responses, vascular dysfunction and activation of connective tissue cells have been reported in genetically-predisposed individuals. Different environmental and occupational factors such as silica and [6]. organic solvents can be involved.

Electron microscopy shows depigmentation, loss of melanocytes and degenerative changes.

#### *2.3.3 Clinical manifestations*

The clinical patterns of the disease include limited cutaneous systemic sclerosis, which is limited to distal limbs, reaches up to the knees and elbows and usually involves the face.

The patients may present only with fibrosis of the fingers. The other pattern, diffuse cutaneous systemic sclerosis, involves the trunk in its early stages and facial involvement is uncommon. This type is often associated with more systemic involvements and a worse prognosis.

Systemic sclerosis can cause diffuse hyperpigmentation that is exacerbated in sun-exposed areas, a specific manifestation of leukoderma. A combination of hypomelanosis and hypermelanosis can be present in the sclerotic and non-sclerotic skin areas of patients with systemic sclerosis, especially on their hands. Leukoderma emerging as complete depigmentation can be comorbid with supravenous hyperpigmentation and perifollicular macules (**Figure 4**). This type of leukoderma can suggest suspected systemic scleroderma.

Histological examinations with an electron microscope shows complete or partial loss of melanocyte pigmentation coupled with degenerative changes.

It is actually a collagen vascular disease with some degree of cutaneous fibrosis that causes skin tightening.

#### *2.3.4 Treatment*

Topical and intralesional steroids are recommended for the inflammatory stages. Topical tacrolimus, calcipotriol and imiquimod have been also used. Combination therapies used in the absence of responses include calcipotriol and betamethasone or imiquimod or low dose PUVA alone or with calcipotriol.

#### **Figure 4.**

*"Salt and pepper" sign Leukoderma with the retention of perifollicular pigmentation in a patient with systemic sclerosis.*

#### **2.4 Hypopigmented mycosis fungoides (HMF)**

#### *2.4.1 Introduction*

HMF is a variant of early MF, which is more prevalent in black individuals. HMF mostly affects ages of 30–40 years, although this type can involve 25–50% of children and adolescents. In fact, it is a prevalent type of MF in children. As a prevalent condition in the Middle East, HMF can be misdiagnosed as pityriasis alba or tinea versicolor in children. A study reported HMF in18 out of 34 subjects and 29 out of 50 adolescents and children [7].

#### *2.4.2 Pathogenesis*

Mycosis fungoides is a cutaneous T-cell lymphoma with a major phenotype of C8+T cells and a pathogenic similarity to vitiligo. Given the absence of clinically hypopigmented lesions in the majority of patients with mycosis fungoides and T cells, presence of cytotoxic T cell phenotypesis not adequate for inducing hypopigmentation. Although electron microscopy shows melanosome degradation in melanocytes and keratinocytes, the large number of normal melanosomes found in melanocytes suggests a defect in melanosome transfer.

#### *2.4.3 Clinical manifestations*

Patients with mycosis fungoides May present with hypopigmented patches and plaques, usually associated with mild erythema and pruritus (**Figure 5**). The lesions are distributed more in the trunk and proximal areas of the limbs, especially in the non-exposed areas. Closer examinations show erythematous lesions.

**Figure 5.** *Mycosis fungoides, hypopigmented patches.*

#### *2.4.4 Treatment*

Repigmentation following treatments can be a sign of their effectiveness. Despite being the only manifestation of conventional mycosis fungoides, HMF is better in terms of its prognosis [8].

One year of treatment with a combination of steroids and tacrolimus, twice a week, was reported to significantly improve hypopigmented patches and cause no recurrence of lesions, and UVB phototherapy, 2–3 times a week, was found to yield proper responses [9].

#### **2.5 Hypopigmented sarcoidosis**

#### *2.5.1 Introduction*

Hypopigmented sarcoidosis is a multisystem granulomatous disease that affects organs such as the lungs, eyes and skin as well as lymph nodes. The exact cause of hypopigmentation in sarcoidosis is unknown. Cutaneous manifestations have been reported in one- quarter to one-third of patients with systemic sarcoidosis. The prevalence of the lesions with different morphologies has been reported as high as 60% in black individuals. The prevalence is also twice in females than in males.

#### *2.5.2 Pathogenesis*

Sarcoidosis can be caused by autoimmune reactions or genetic processes given the existing racial and ethnic differences. HLA haplotype diversity patterns can explain different manifestations between different races. This disorder is histopathologically categorized as a granulomatous disease given the non-caseating granulomas found in the dermis. Electron microscopy also shows vacuolated melanocytes and decreases in the number of melanosomes in keratinocytes. Granulomas mainly include epithelioid cells and occasionally giant cells, with lymphocytic infiltration around granulomasin the absence of caseous necrosis.

#### *2.5.3 Clinical manifestations*

The most prevalent skin manifestations of sarcoidosis include small erythematous-violaceous papules 3–5 mm. Sarcoidosis often initiates in an acute state and then becomes chronic. With a peripheral scaly marginand a hypopigmented center (**Figure 6**), the annular lesions are usually limited to the head and neck with a poor prognosis. A rare cutaneous form with patches or plaques usually appearing 1–10 mm in size mainly involves the trunk and face. Erythematous papules in the center of the patches resemble a fried egg [10].

The patients are often asymptomatic and usually diagnosed through radiological examinations. A skin biopsy and pathological examinations may also be ultimately required.

#### *2.5.4 Treatment*

Although acute sarcoidosis is a self-healing conditions, cutaneous sarcoidosis with systemic involvement can be treated with 1 mg/kg/day of prednisolone as an oral steroid to cleanse the skin lesions. The localized skin manifestations can be treated only with topical steroids or intralesional injections. Anti-TNF biologic medications can be used as alternatives to steroids, especially when steroids are

*Hypomelanosis Secondary to Cutaneous Inflammation DOI: http://dx.doi.org/10.5772/intechopen.96256*

#### **Figure 6.**

*Cutaneous sarcoidosis; clinical variants, the hypopigmented variant is more noticeable in individuals with a darkly-pigmented skin.*

contraindicated. Hypopigmented cutaneous sarcoidosis is responsive to minocycline [11] and can be treated with 8-methoxypsoralen [12] and long-wave ultraviolet light.

#### **2.6 Lichen Striatus**

#### *2.6.1 Introduction*

Lichen striatus is a benign self-limiting dermatosis with an unknown etiology. It is more prevalent in children than in other age groups, it is acquired and unilaterally occurs along the lines of blaschko. Although the lesions are often transient, they may be of a prolonged form.

Lichen striatus is associated with vitiligo or atopic dermatitis. It mainly affects children at an age of 3.5 years, although it may occur in children of 4 months to 10 years of age.

#### *2.6.2 Clinical manifestations*

Lichen striatus usually manifests itself as smooth and scaly or hypopigmented flat-topped papules, which are 2-4 mm in size and initially inflammatory (**Figure 7**). The lesions appear as continuous or interrupted flat papules along the lines of blaschko within 2–3 weeks. The eruptions, being mainly distributed in the limbs, especially the lower limbs, normally leave a long-lasting hypopigmentation in 50% of the cases. According to recent studies in India, lichen striatus causes hypopigmentation in approximately 1.7% of the patients [13].

#### *2.6.3 Treatment*

No treatments are normally required given the benign and self-limiting nature of the disease. Tacrolimus ointment has been found to speed up the relief and cause complete healing without skin sequelae.

#### **Figure 7.**

*Lichen striatus: Linear streaks on the leg alongthe lines of Blaschko, comparing numerous small, flat-topped tan (hypopigmented) papules.*

#### **3. Conclusion**

Numerous inflammatory skin diseases can cause pigmentation disorders, which suggests that despite multiple inflammatory disease of skin, ultimately through the activation of inflammatory agents located in the skin, such as T cells, cytokines and other inflammatory cells that lead to disregulation of melanogenesis system.

However, the exact mechanism of PIH is not known and further studies are needed. Despite advance in treating the cause of the hypomelanosis, but PIH is still a challenge for dermatologists. Appropriate treatment for PIH is to identify the underlying cause and treat it, with applying symptomatic therapy.

#### **Conflict of interest**

The author declares no conflict of interest.

#### **Author details**

Behzad Dalvand Artina Skin and Hair Clinic, Tehran, Iran

\*Address all correspondence to: dalvandb@yahoo.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Hypomelanosis Secondary to Cutaneous Inflammation DOI: http://dx.doi.org/10.5772/intechopen.96256*

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## Section 7
