Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 19, Issue 3, 2019

Background: The conserved Wnt/β-catenin signaling pathway is responsible for multiple functions including regulation of stem cell pluripotency, cell migration, self-renewability and cell fate determination. This signaling pathway is of utmost importance, owing to its ability to fuel tissue repair and regeneration of stem cell activity in diverse organs. The human adult stem cells including hematopoietic cells, intestinal cells, mammary and mesenchymal cells rely on the manifold effects of Wnt pathway. The consequences of any dysfunction or manipulation in the Wnt genes or Wnt pathway components result in specific developmental defects and may even lead to cancer, as it is often implicated in stem cell control. It is absolutely essential to possess a comprehensive understanding of the inhibition and/ or stimulation of the Wnt signaling pathway which in turn is implicated in determining the fate of the stem cells. Results: In recent years, there has been considerable interest in the studies associated with the implementation of small molecule compounds in key areas of stem cell biology including regeneration differentiation, proliferation. In support of this statement, small molecules have unfolded as imperative tools to selectively activate and inhibit specific developmental signaling pathways involving the less complex mechanism of action. These compounds have been reported to modulate the core molecular mechanisms by which the stem cells regenerate and differentiate. Conclusion: This review aims to provide an overview of the prevalent trends in the small molecules based regulation of stem cell fate via targeting the Wnt signaling pathway.

Objective: Neuroinflammatory disease is a general term used to denote the progressive loss of neuronal function or structure. Many neuroinflammatory diseases, including Alzheimer’s, Parkinson’s, and multiple sclerosis (MS), occur due to neuroinflammation. Neuroinflammation increases nuclear factor-ΚB (NF-ΚB) levels, cyclooxygenase-2 enzymes and inducible nitric oxide synthase, resulting in the release of inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). It could also lead to cellular deterioration and symptoms of neuroinflammatory diseases. Recent studies have suggested that curcumin (the active ingredient in turmeric) could alleviate the process of neuroinflammatory disease. Thus, the present mini-review was conducted to summarize studies regarding cellular and molecular targets of curcumin relevant to neuroinflammatory disorders. Methods: A literature search strategy was conducted for all English-language literature. Studies that assessed the various properties of curcuminoids in respect of neuroinflammatory disorders were included in this review. Results: The studies have suggested that curcuminoids have significant anti- neuroinflammatory, antioxidant and neuroprotective properties that could attenuate the development and symptom of neuroinflammatory disorders. Curcumin can alleviate neurodegeneration and neuroinflammation through multiple mechanisms, by reducing inflammatory mediators (such as TNF-α, IL-1β, nitric oxide and NF-ΚB gene expression), and affect mitochondrial dynamics and even epigenetic changes. Conclusion: It is a promising subject of study in the prevention and management of the neuroinflammatory disease. However, controlled, randomized clinical trials are needed to fully evaluate its clinical potential.

Background And Objective: Osteoporosis is a common bone disorder that increases susceptibility to fragility bone fractures. The clinical and public health repercussions of osteoporosis are huge due to the morbidity, mortality, and cost of medical care linked with fragility fractures. Clinical assessment of osteoporotic risk factors can help to identify candidates at an early stage that will benefit from medical intervention and potentially lowering the morbidity and mortality seen with fractures and complications. Given this, research is ongoing to evaluate the association of osteoporosis with some novel or less well-studied risk factors/bio-markers such as uric acid (UA). Discussion: Uric acid’s antioxidant activity has been proposed to be one of the factors responsible for increasing longevity and lowering rates of age-related cancers during primate evolution, the level of which increased markedly due to loss of uricase enzyme activity (mutational silencing). Accumulated evidence shows that oxidative stress is the fundamental mechanism of age-related bone loss and acts via enhancing osteoclastic activity and increasing bone resorption. Antioxidant substances such as ascorbic acid scavenge free radicals are positively related to bone health. Thus, it is hypothesized that uric acid holds bone-protective potential owing to its potent antioxidative property. Several correlation studies have been conducted globally to investigate the relationship between serum uric acid with bone mineral density and osteoporosis. Few pre-clinical studies have tried to investigate the interaction between uric acid and bone mineral density and reported important role played via Runt-related transcription factor 2 (RUNX2)/core-binding factor subunit alpha-1 (CBF-alpha-1), Wingless-related integration site (Wnt)-3a/β-catenin signaling pathway and 11β Hydroxysteroid Dehydrogenase type 1. Conclusion: In this review, the authors provided a comprehensive summary of the literature related to association studies reported in humans as well work done until date to understand the potential cellular and molecular mechanisms that interplay between uric acid and bone metabolism.

Background: There is a strong association between liver diseases and diabetes (DM) which is higher than expected by a correlation between two very common diseases. Liver diseases may occur as a result of diabetes, and the reverse is true as well. Aim: To review the etiology of this association between liver diseases and diabetes and how to diagnose it. Methods: Studies that identified this association between liver diseases and diabetes and how to diagnose it was reviewed. Results: This association can be divided into the following categories: liver disease related to diabetes (Diabetic hepatopathy), hepatogenous diabetes (HD), and liver diseases that occur in conjunction with Diabetes mellitus. Two hours after glucose loading is the best screening test for HD. HbA1c may neither be suitable for diagnosis nor monitoring of diabetes that links liver disease. Conclusion: NAFLD, hepatogenous diabetes, glycogenic hepatopathy and diabetic hepatosclerosis are the most important association between liver diseases and diabetes. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is the best screening test for HD due to the fact that fasting glucose can be normal early in the disease. The tool used for diabetes monitoring depends on stage and severity of liver condition.

Background: Drugs of abuse affect both central nervous system (CNS) and peripheral immune function. Besides the involvement of dopamine and glutamate systems, chronic exposure to drugs of abuse alters immune homeostasis, promoting a pro-inflammatory status. At the same time, impaired peripheral immunity leads to an increased susceptibility to infections in drug abusers. Discussion: There is evidence that certain drugs, such as opioids, activate microglial cells and astrocytes which, in turn, provoke central neuroinflammation. Particularly, opioids bind the Toll-like receptor (TLR)-4 with increased expression of nuclear factor kappa-light-chain-enhancer of activated B cells and release of pro-inflammatory cytokines. Peripheral mediators released by immune cells also contribute to aggravate central neuroinflammation. Conclusion: These are based either on the inhibition of TLR-4 activation by drugs of abuse or on the correction of dopamine and glutamate pathways. Finally, a hypothetic nutraceutical intervention with polyphenols in view of their anti-inflammatory and anti-oxidant properties will be outlined as an adjuvant treatment for drugs of abuse-related disorders.

Objective: The aim of this work was to evaluate the antihyperglycemic activity of aerial parts aqueous extract (A.P.A.E) of Mentha pulegium (M. pulegium) on blood glucose levels in normal and streptozotocin(STZ)-induced diabetic rat. The glucose tolerance was evaluated in normal rats. Moreover, the histological sections and morphometric analysis at the liver and pancreas have been carried out in this investigation both in normal and STZ-diabetic rats. Methods: The effect of A.P.A.E of M. pulegium (20 mg/kg) on blood glucose levels was investigated in normal and diabetic rats (n=6). Histopathological changes in liver and pancreas were examined under phase contrast microscope and a preliminary screening for various bioactive constituents was realized according to standard methods. Key Findings: Both single and repeated oral administration of A.P.A.E (20 mg/kg) caused a significant reduction in blood glucose levels in STZ-diabetic rats (p<0.0001). The morphometric analysis and histological sections realized in pancreas and liver have showed the beneficial effect of the A.P.A.E in cellular population. According to oral glucose tolerance test (OGTT), the aqueous extract has revealed an improvement of glucose tolerance in normal rat. Furthermore, the preliminary phytochemical screening of A.P.A.E of M. pulegium has demonstrated the presence of various metabolite compounds including polyphenols, flavonoids, terpenoids tannins, cyanidins, sesquiterpenes, and glycosides. Conclusion: We conclude that the A.P.A.E of M. pulegium (20 mg/kg) exhibits a potent antihyperglycemic activity in STZ diabetic rats.

Background: Patients with hematological malignancies undergoing cytotoxic chemotherapy are susceptible to develop invasive fungal infections particularly Aspergillus and Candida spp. Early detection of these infections is required to start immediate antifungal therapy and increase the survival of these patients. Method: Our study included consecutive patients of any age with hematologic malignancies who were hospitalized to receive chemotherapy and suffer from persistent fever (rectal temperature >38.5°C) for more than 5 days despite receiving broad-spectrum antibiotics. A whole blood sample was taken and sent for blood culture. PCR was also conducted for Aspergillus and Candida species. Results: One hundred and two patients were investigated according to the inclusion criteria. The most common hematologic malignancy was AML affecting 38 patients (37.2%). Six patients were diagnosed with invasive fungal infections (A. fumigatus n=3, C. albicans n=2, A. flavus n=1) by PCR (5.8%) while blood culture showed fungus only in 1 patient. Three more cases were known as probable IFI since they responded to antifungal therapy but the PCR result was negative for them. AML was the most prevalent malignancy in IFI patients (83.3%) and odds ratio for severing neutropenia was 21.5. Odds for each of the baseline characteristics of patients including gender, age>60, diabetes mellitus, previous IFI, history of using more than 3 antibiotics, antifungal prophylaxis, episodes of chemotherapy> 8 and chemotherapy regimen of daunarubicin+cytarabine were calculated. Conclusion: We found that multiplex real-time PCR assay is more accurate than blood culture in detecting fungal species and the results are prepared sooner. Among all factors, the only type of cancer (AML) and severe neutropenia, were found to be risk factors for the development of fungal infections in all hematologic cancer patients and previous IFI was a risk factor only AML patients.

Background: Production of tumor necrosis factor (TNF)-α by inflammatory cells in lesions is the hallmark of the pathogenesis of rheumatoid arthritis (RA). Regulation of inflammatory responses in knee joints of patients with RA is critical for improving severe symptoms. Flavonoids have inhibitory effects on the acute and chronic inflammatory responses caused by TNF-α. The flavonoid quercetin (QUER) is one of the most prominent dietary antioxidants. Objective: The present study investigated the preventive and therapeutic effects of QUER on inflammatory responses in collagen-induced arthritis (CIA) in mice. Methods: Mice with CIA, a mouse model for RA, were treated with QUER orally three times a week either from the second immunization with collagen (day 21) or day 28 when symptoms of CIA had developed midway. Results: In both cases, inflammation-related clinical scores of knee joints were significantly reduced by treatment with QUER. Histological analyses showed that the representative characteristics of RA, such as damage to interchondral joints, infiltration of inflammatory cells, and pannus formation, were significantly reduced by QUER treatment. Oral administration of QUER significantly decreases lipopolysaccharide (LPS)-induced TNF-α production in a dose-dependent manner. Expression of TNF- α mRNA in knee joints was decreased in QUER-treated mice, compared with those of CIA controls. Conclusion: These results suggest that oral administration of QUER might effectively improve symptoms of RA.

Objective: Experimental autoimmune encephalomyelitis (EAE) is a widely used model for multiple sclerosis. The present study has been designed to compare the efficiencies of oral and intraperitoneal (IP) administration of D-aspartate (D-Asp) on the onset and severity of EAE, the production of neurosteroids, and the expression of neurosteroid receptors and inflammatory mediators in the brain of EAE mice. Methods: In this study, EAE was induced in C57BL/6 mice treated with D-Asp orally (D-Asp-Oral) or by IP injection (D-Asp-IP). On the 20th day, brains (cerebrums) and cerebellums of mice were evaluated by histological analyses. The brains of mice were analyzed for: 1) Neurosteroid (Progesterone, Testosterone, 17β-estradiol) concentrations; 2) gene expressions of cytokines and neurosteroid receptors by reverse transcription polymerase chain reaction, and 3) quantitative determination of D-Asp using liquid chromatography-tandem mass spectrometry. Further, some inflammatory cytokines and matrix metalloproteinase-2 (MMP-2) were identified in the mouse serum using enzyme-linked immunosorbent assay kits. Results: Our findings demonstrated that after D-Asp was administered, it was taken up and accumulated within the brain. Further, IP injection of D-Asp had more beneficial effects on EAE severity than oral gavage. The concentration of the testosterone and 17β-estradiol in D-Asp-IP group was significantly higher than that of the control group. There were no significant differences in the gene expression of cytokine and neurosteroid receptors between control, D-Asp-IP, and D-Asp-Oral groups. However, IP treatment with D-Asp significantly reduced C-C motif chemokine ligand 2 and MMP-2 serum levels compared to control mice. Conclusion: IP injection of D-Asp had more beneficial effects on EAE severity, neurosteroid induction and reduction of inflammatory mediators than oral gavage.

Objective: Adrenal incidentalomas are diagnosed incidentally during radiological screenings and require endocrinological investigations for hormonal activity and malignancy. In certain studies, it has been reported that non-functional incidentalomas can be associated with high adipocytokines levels affecting the insulin resistance just like the adipose tissue with metabolic syndrome. Here, we studied serum adipocytokine levels including leptin, resistin, visfatin, omentin 1 and adiponectin in subjects with non-functional adrenal incidentaloma. Methods: Seventy-seven (77) patients (Female 57; Male 20) with non-functional adrenal incidentaloma (NFAI) were enrolled in the study. All patients’ past medical history, physical examination including Body Mass Index (BMI) and waist circumference were performed. The patients’ demographic, radiologic, hormonal and biochemical parameters were recorded. To compare the parameters, a control group (CG) (n=30) was formed from healthy volunteers. Both groups were matched for age, gender, waist circumference and BMI. Serum adipocytokines including leptin, resistin, visfatin, omentin 1 and adiponectin were measured quantitatively by ELISA. Fasting plasma glucose, insulin, sodium, potassium, cortisol, adrenocorticotropic hormone (ACTH), lipid profiles, and dehidroepiandrostenedion sulphate (DHEAS) were measured. Results: Mean age of the patients was 52.2±10.4 years. BMI and waist circumference of NFAI patients were 26.2±3.28 kg/m2 and 90.2 ±7.5cm, respectively. The mean age of the control group was 48.0±8.16. BMI and waist circumference values for the control group were 25.3±3.5 kg/m2 and 88.3±9.6 cm, respectively. When both groups were compared for age, gender, BMI and waist circumference were non-significant (p>0.05). Serum fasting insulin, total cholesterol, LDL, triglyceride levels of the NFAI group were significantly higher than CG (p<0.05). The insulin resistance index (HOMAIR) values of the NFAI subjects were found to be higher than CG (2.5±1.37, 1.1±0.3 p=0.00). Resistin level of NFAI group was also found to be higher than CG [286.6 ng/L vs. 197 ng/L; (P=0,00)], respectively. Leptin levels of NFAI were significantly higher than CG [441.1 ng/mL vs. 186.5 ng/mL; (P=0.00)] respectively. Adiponectin levels were significantly reduced in the NFAI group than in the CG [10.7 mg/L vs. 30.8 mg/L; (P=0.00)]. Comparision of visfatin and omentin levels was nonsignificant. Conclusion: In this study on subjects with non-functional adrenal incidentaloma, we found not only significantly decreased serum adiponectin levels but also increased leptin, resistin levels as well as dyslipidemia, hypertension and high insulin resistance index. All of which could affect insulin resistance and cardiovascular risk factors. The underlying mechanisms of these findings are unknown, hence further studies are needed.

Aim: The study was conducted in order to examine the sex-specific association of serum uric acid (SUA) levels with elevated serum alanine aminotransferase (ALT) in a Taiwanese military cohort. Methods: We made a cross-sectional examination of the sex-specific relationship using 6728 men and 766 women, aged 18-50 years from a large military cohort in Taiwan. SUA levels within the reference range (<7.0 mg/dL for men and <5.7 mg/dL for women respectively) were divided into quartiles and SUA levels greater than the upper reference limits were defined as hyperuricemia. Elevated ALT levels were defined as ≥40 U/L. Multivariate logistic regression analysis was performed to determine the association between each SUA category and elevated ALT levels in men and women, respectively. Results: The prevalence of hyperuricemia and elevated ALT in men were 18.7% and 12.7%, respectively, and in women were 3.3% and 2.1%, respectively. As compared with the lowest SUA quartile, hyperuricemia was associated with elevated ALT in men (odds ratios (OR): 1.62, 95% confidence intervals (CI): 1.19-2.20) after controlling for age, service specialty, body mass index, metabolic syndrome components, current cigarette smoking, alcohol intake status, and weekly exercise times, but the associations for the other SUA quartiles were null. By contrast, the associations of hyperuricemia (OR: 0.81, 95% CI: 0.10-6.64) and the other SUA quartiles with elevated ALT were null in women. Conclusion: Our findings suggest that the relationship between each SUA level and elevated ALT may differ by sex among military young adults. The mechanism for the sex difference requires further investigations.

Background: Neonatal hypoxic ischemic encephalopathy (HIE) is a potentially devastating disorder associated with significant mortality and long-term morbidity. Objective: The aim of this study was to study the role of vitamin D as an adjuvant therapy for management of neonatal HIE. Patients and Methods: This study was carried out on 60 neonates with HIE grade II who were diagnosed according to modified Sarnat staging and were divided in to 2 groups: Group I: Included 30 neonates with Sarnat grade II HIE who received single daily oral dose of vitamin D3 (1000 IU) for 2 weeks in addition to daily subcutaneous (SC) human recombinant erythropoietin (2500 IU/kg) for 5 days and IM or IV magnesium sulphate 250 mg/kg within half an hour of birth, and subsequently 125 mg/kg at 24 and 48 hours of life. Group II: Included 30 neonates with HIE grade II who received erythropoietin and magnesium sulphate as group I but without vitamin D. Two blood samples were taken from all neonates included in both groups; the 1st at diagnosis and the 2nd after 2 weeks of therapy. This study included also 30 healthy neonates as a control group. All neonates included in this study were subjected to: complete clinical examination with assessment of Apgar score at 5 and 10 minutes, measurement of arterial blood gases and serum 25 (OH) vitamin D, calcium, phosphorus, S100-B and IL-17 levels. Results: Before therapy, there were no significant differences between group I and II in PH, PO2 and PCO2 (p= 0.294, 0.462, 0.758 respectively), but after 2 weeks of therapy, there were significantly higher PH levels in group I compared with group II (p <0.001) while there were no significant differences between group I and II regarding PO2 and PCO2. Before therapy, there were no significant differences in serum 25(OH) vitamin D levels between group I and II while there were significantly lower serum 25(OH) vitamin D levels in group I and II compared with controls (P1; comparison between group I and II = 0.742, P2; comparison between group I and controls = 0.001 and P3; comparison between group II and controls = 0. 001). There were no significant differences between group I and II and between group I and II and control as regard serum calcium (P1= 0.943, P2= 0.875 and P3= 0.764) and phosphorus (P1= 0.862, P2= 0.921, P3= 0.786). There were no significant differences between group I and II regarding serum IL-17 levels while there were significantly lower serum IL-17 levels in group I and II compared with controls (P1 = 0.457, P2 = 0.043 and P3 = 0.023). Before therapy, there were no significant differences in serum S100-B levels between group I and II while there were significantly higher serum S100-B levels in group I and II compared with control (P1 = 0.381, P2 = 0.001 and P3= 0.001) but after therapy, there were significantly higher S100-B levels in group II compared with group I and significantly higher S100-B levels in group I and II compared with control (P1= 0.001, P2= 0.043, P3 = 0.001). There were significant negative correlations in group I between serum S100-B and PH and between S100-B and serum vitamin D before and after therapy. Conclusion: Vitamin D was found to improve the cases of group I as demonstrated by the reduction of serum S100-B levels after vitamin D therapy. Recommendations: Extensive multicenter studies are required on a large number of patients with Sarnat grade II HIE with longer duration of follow up to give valid recommendations about the use of vitamin D as an adjuvant therapy in Sarnat grade II HIE.

Objective: Gut microbiota is currently targeted for various diseases especially metabolic disorders such as diabetes. Our strategy is to alter gut microflora via specific antibiotic to reduce load of inflammation in the liver that increases as a result of high carbohydrate diet. Th1, Th17 and Treg are important immune cell types which decide the type of inflammatory response. Liver is tolerogenic in nature with low Th17/Treg ratio. In diabetics, this ratio decreases even more, and can cause liver trauma. Method: The present study tries to find relationship between gut flora and immune cells such as Th1/Th17/Treg and their role in liver metabolism using diet induced diabetic mice model. Result: Upon alteration of flora using Cefdinir in different forms, one could help lower the level of Treg cells thus increasing the ratio. Gut flora is strongly associated with the immunity in the liver. Targeted alteration of gut flora helps us to restore insulin sensitivity. Conclusion: Colon targeted Cefdinir gives more promising results, opens colonic bacteria as target for improving gut, liver inflammation and insulin sensitivity.

Backgroud: The present study aimed to investigate the association between immune cells and gestational diabetes mellitus (GDM) and identify a reasonable predictor of insulin resistance in women with GDM. Objective: The clinical and biochemical characteristics of 124 women with GDM and 168 healthy pregnant women were compared. Methods: The percentage of immune cells in the blood of the subjects was analyzed by flow cytometry. Pearson’s correlation analysis revealed the correlation between the percentage of B lymphocytes and insulin resistance. A cutoff point was determined for the percentage of B lymphocytes, based on insulin resistance, using receiver operating characteristic (ROC) curves. Results: Compared to the healthy pregnant women, the percentages of B lymphocytes and IgA produced by B-cells were significantly different in women with GDM. The percentage of B lymphocytes was positively related to insulin resistance.The number of 14.05% of B lymphocytes was an optimal cutoff point that predicted the insulin resistance in women with GDM. Conclusion: The percentage of B lymphocytes was positively associated with insulin resistance, and hence, might serve as an appropriate predictor of insulin resistance in women with GDM.

Background: Rosacea is a frequently seen chronic disease. Certain allergens, some foods and beverages are known to trigger symptoms of rosacea. Objective: We aimed to assess if nickel sensitivity is more common in rosacea patients than the normal population. Method: Fourty patients with rosacea and 40 healthy age and sex-matched volunteers were included in the study. From European standard patch test series, test units with nickel were applied on the skin of the upper back. According to the scheme of the International Contact Dermatitis Research Group (ICDRG), test results were evaluated at 48th, 72th and 96th hours. Seven days later, reevaluation was done for late reactions. Statistical analyses were done by using Statistics package for Social Sciences (SPSS) 17 package program and p<0.05 was accepted as statistically significant. Results: Female/male ratio was 34/6 in patient group and 32/8 in control group. Mean age of the patient group and the control group were 39.97±12.65 (18-65 years), 40.82±11.79 (19-68 years), respectively. Age and sex distributions were found to be statistically similar. Nickel allergy in the patient and control group was found to be 52.5%, 22.5% respectively and the difference between groups was statistically significant (p=0. 006). Conclusion: Our results showed that there may be an association between nickel sensitivity and rosacea. Nickel sensitivity may be one of the underlying pathology or a triggering factor of the rosacea. Nickel restricted diet and avoiding the use of nickel-containing jewellery and piercings may extend the remission periods.

Background: Inflammatory bowel diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), are described as a chronic inflammation of the small intestine and colon, caused by a dysregulated immune response to host intestinal microbiota in genetically susceptible subjects. Objective: The aim of this study was to compare probiotic therapy versus placebo in Oxidative Stress Values and clinical features in patients affected by IBD. Method: Forty (40) patients previously diagnosed for IBD were recruited and randomized to receive probiotics (test group, n=20) or placebo (control group, n=20) administered for 90 days. Subjects in both the groups were assessed for overall oxidant ability (d-ROMs test) and for the antioxidant response (BAP test): data were reported at baseline, after 1 and 3 months. Additional data from anamnesis and haematological investigation were also reported during the study. Results: d-ROM assay clearly showed that the values observed in the test group were significantly improved, leading to oxidative stress values which are not pathological. The test group showed increasing BAP values, thus confirming the overall improvements of patients ‘health following administration of probiotics. Conclusion: Oral administration of the specific probiotics demonstrated its efficacy and safety on patients affected by IBD.

Background: Neurofibromatosis type 1 is an autosomal dominant disorder characterized by an increased incidence of tumors, including endocrine ones. Primary hyperparathyroidism can be rarely caused by a parathyroid carcinoma; these patients are generally characterized by severe symptoms, large neck lesions and high levels of PTH and calcium. We report a case of hyperparathyroidism due to parathyroid carcinoma in a patient affected by neurofibromatosis type 1. A systematic review of the literature was also conducted. Patient Findings: A 56-year-old woman was referred for a 13 mm-nodular lesion of the neck incidentally discovered on ultrasound examination and mild hyperparathyroidism. A 99mTctetrofosmin/ pertechnetate subtraction scintigraphy was negative for parathyroid disease. Given the absence of suspicious ultrasound finding, a fine-needle aspiration cytology was performed with iPTH determination in the aspirate, confirming the parathyroid origin of the lesion. The patient underwent left inferior parathyroidectomy with intraoperative monitoring of iPTH and became normocalcemic. On histopathological examination, parathyroid carcinoma presenting at the resection margin was diagnosed, thus a surgery revision was requested. Conclusion: Even if literature does not support a syndromic association between neurofibromatosis type 1 and primary hyperparathyroidism, the benefit of precociously diagnosing and treating this condition may outweigh costs associated with screening. This case report moreover demonstrates that sometimes clinical, laboratory and imaging aspects suspicious for cancer may be missing. A prompt referral to a high-volume center is crucial for the management of those cases of incidental histopathological diagnosis.