Challenges and pitfalls in the management of endocrine toxicities from immune checkpoint inhibitors: a case presentation of synchronous thyrotoxicosis and primary adrenal insufficiency in a melanoma patient.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the therapeutic approach to several solid tumors, becoming the standard of care for cancer treatment in different disease settings. Despite the fact that these agents are better tolerated than conventional chemotherapy, their use is associated with a specific toxicity profile, so-called immune-related adverse events (irAEs), that can involve several organs. Endocrine irAEs are among the most frequent toxicities (around 10 to 16%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Some of them may be life-threatening if not promptly recognized (such as diabetic ketoacidosis and acute adrenal crisis). CASE PRESENTATION: A 55-year-old woman with a personal history of euthyroid Hashimoto's thyroiditis was diagnosed with a metastatic melanoma, BRAF wild type. Under treatment with anti-PD-1 pembrolizumab, she developed thyrotoxicosis followed by hypothyroidism due to destructive thyroiditis and concurrent primary adrenal insufficiency due to adrenalitis. CONCLUSIONS: The simultaneous occurrence of adrenal and thyroid autoimmune diseases, resembling autoimmune polyendocrine syndrome type 2, may occur as a rare but serious side effect of ICI treatment. It often presents with abrupt onset and rapid evolution towards polyglandular insufficiency. Physicians should be aware of the potential association of two or more endocrine disorders and careful monitoring of endocrine function is needed during ICI therapy.

Polychlorinated Biphenyls (PCBS)-induced oxidative stress and inflammation in human thyrocytes: involvement of AhR and NRF-2/HO-1 pathway.

PURPOSE: In this in vitro study, we investigated the effects of polychlorinated biphenyls (PCBs) on human thyrocytes, with a focus on the involvement of AhR, a key player in xenobiotic response, and the anti-oxidant Nrf-2/HO-1 pathway. METHODS: Primary cultured thyrocytes were exposed to the dioxin-like congeners PCB118 and PCB126 at 2.5 and 5 µM concentrations. mRNA expression was assessed by real-time PCR, and protein expression by Western Blot and ELISA, while protein quantification was assessed by densitometric analysis. RESULTS: In cultured thyrocytes, PCB118 and PCB126 induced a significant (P < 0.01) increase of mRNA and protein levels of the pro-inflammatory cytokines IL-1beta and IL-6, while reducing those of thyroglobulin (TG) and NIS (p < 0.05), indicating down-regulation of these thyroid-specific genes in PCB-induced inflammation. ROS production also increased (p < 0.001). mRNA levels of AhR and the downstream molecules cytochrome P4501A, Nrf-2/HO-1 increased (p < 0.001), as well as related protein levels (p < 0.01), suggesting the activation of AhR and Nrf-2 pathways in response to PCBs exposure. AhR silencing decreased AhR-related gene expression and restored NIS and TG expression, while reducing inflammatory cytokines and oxidative stress markers (p < 0.05). CONCLUSIONS: Dioxin-like PCBs (PCB118 and PCB126) may promote inflammation and oxidative stress in thyrocytes, impairing the expression of genes that are key players of thyroid function. These effects can be partially attributed to the activation of the AhR and Nrf-2 pathways. These data may contribute to explain the mechanisms underlying thyroid toxicity of PCBs, highlighting the potential role of these pollutants as a trigger of autoimmune thyroid inflammation and damage.

Adrenal Cushing's syndrome: diagnosis and management in a 10-year-old boy with Carney complex.

INTRODUCTION: ACTH-independent Cushing's Syndrome (CS) is very rare condition in children. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of CS, which in most cases occurs in the context of Carney complex (CNC). CNC is an autosomal-dominantly inherited genetic syndrome, usually due to pathogenic variants of the PRKAR1A (regulatory subunit R1A of the protein kinase A) gene. The clinical picture is characterized by spotty skin pigmentation, cardiac, cutaneous and mammary myxomas, melanocytic schwannomas, endocrinopathies and tumours of the endocrine glands (mostly adrenal, pituitary and thyroid). CASE PRESENTATION: A 10-year-old boy first came to our Outpatient clinic due to severe obesity. During the first three months of follow-up the height growth rate was normal, but the response to dietary-behavioural indications was poor in term of weight loss. Later, 10 months after the last evaluation, there was evidence of significant worsening of obesity, growth failure, arterial hypertension and the occurrence of red skin striae at the trunk and root of the limbs. Endocrinological causes of obesity associated with growth failure were investigated. The circadian rhythm of cortisol, ACTH and cortisoluria were suggestive of ACTH-independent hypercortisolaemia. Iatrogenic causes were ruled out. Adrenal ultrasound and computer tomography initially indicated the presence of a nodule or hyperplasia of the medial arm of the left adrenal gland. Conversely, magnetic resonance imaging showed a significant increase in the global dimensions of the adrenals with a bilateral micronodular appearance. Considering the association between ACTH-independent hypercortisolism and PPNAD, a genetic investigation was performed, which found a pathogenic variant of the PRKAR1A gene. Patient started, and well tolerated, therapy with metyrapone during a two-year follow-up. The clinical picture has slightly improved, cortisoluria returned and remains within normal limits, but ACTH suppression persists. CONCLUSION: This is the first report on the clinical and biochemical effects of 2-year medical treatment with metyrapone of PPNAD-related hypercortisolaemia in a paediatric patient with CNC. Currently, there are no established protocols for the management of hypercortisolism in PPNAD and data are scarce especially in the paediatric field. Medical therapies may play a role in reducing the need, at least initially, for bilateral adrenalectomy. However, further studies are needed to clarify this aspect. In cases of CS due to PPNAD in which medical therapy was the initial approach, in the absence of clear clinical, auxological and biochemical improvements, metyrapone may have to be discontinued in favour of another approach, including surgery.

Epidemiological analysis to identify predictors of X-linked hypophosphatemia (XLH) diagnosis in an Italian pediatric population: the EPIX project.

PURPOSE: X-linked hypophosphatemia (XLH) is a rare multi-systemic disease characterized by low plasma phosphate levels. The aim of this study was to investigate the annual XLH prevalence and internally evaluate predictive algorithms' application performance for the early diagnosis of XLH. METHODS: The PediaNet database, containing data on more than 400,000 children aged up to 14 years, was used to identify a cohort of XLH patients, which were matched with up to 10 controls by date of birth and gender. The annual prevalence of XLH cases per 100,000 patients registered in PediaNet database was estimated. To identify possible predictors associated with XLH diagnosis, a logistic regression model and two machine learning algorithms were applied. Predictive analyses were separately carried out including patients with at least 1 or 2 years of database history in PediaNet. RESULTS: Among 431,021 patients registered in the PediaNet database between 2007-2020, a total of 12 cases were identified with a mean annual prevalence of 1.78 cases per 100,000 patients registered in PediaNet database. Overall, 8 cases and 60 matched controls were included in the analysis. The random forest algorithm achieved the highest area under the receiver operating characteristic curve (AUC) value both in the one-year prior ID (AUC = 0.99, 95% CI = 0.99-1.00) and the two-year prior ID (AUC = 1.00, 95% CI = 1.00-1.00) analysis. Overall, the XLH predictors selected by the three predictive methods were: the number of vitamin D prescriptions, the number of recorded diagnoses of acute respiratory infections, the number of prescriptions of antihistamine for systemic use, the number of prescriptions of X-ray of the lower limbs and pelvis and the number of allergology visits. CONCLUSION: Findings showed that data-driven machine learning models may play a prominent role for the prediction of the diagnosis of rare diseases such as XLH.

Factors associated with disease control failure in acromegaly patients treated with pegvisomant: an ACROSTUDY analysis.

Purpose: The aim of this study was to examine the probability of achieving acromegaly disease control according to several patient-, disease- and treatment-related factors longitudinally. Methods: We analyzed data from ACROSTUDY, an open-label, noninterventional, post-marketing safety surveillance study conducted in 15 countries. A total of 1546 patients with acromegaly and treated with pegvisomant, with available information on baseline IGF-1 level, were included. Factors influencing IGF-1 control were assessed up to 10 years of follow-up by mixed-effects logistic regression models, taking into account changing values of covariates at baseline and at yearly visits. Twenty-eight anthropometric, clinical and treatment-related covariates were examined through univariate and multivariate analyses. We tested whether the probability of non-control was different than 0.50 (50%) by computing effect sizes (ES) and the corresponding 95% CI. Results: Univariate analysis showed that age <40 years, normal or overweight, baseline IGF-1 <300 µg/L or ranged between 300 and 500 µg/L, and all pegvisomant dose <20 mg/day were associated with a lower probability of acromegaly uncontrol. Consistently, in multivariate analyses, the probability of uncontrolled acromegaly was influenced by baseline IGF-1 value: patients with IGF-1 <300 µg/L had the lowest risk of un-controlled acromegaly (ES = 0.29, 95% CI: 0.23-0.36). The probability of acromegaly uncontrol was also lower for values 300-500 µg/L (ES = 0.37, 95% CI: 0.32-0.43), while it was higher for baseline IGF-1 values ≥700 µg/L (ES = 0.58, 95% CI: 0.53-0.64). Conclusion: Baseline IGF-l levels were a good predictor factor for long-term acromegaly control. On the contrary, our data did not support a role of age, sex, BMI and pegvisomant dose as predictors of long-term control of acromegaly. Significance statement: Among factors that could influence and predict the efficacy of pegvisomant therapy in controlling acromegaly, a central role of baseline IGF-1 values on the probability of achieving a biochemical control of acromegaly during the treatment with pegvisomant was identified, in a real-life setting.

The unusual association of Graves' disease, chronic spontaneous urticaria, and premature ovarian failure: report of a case and HLA haplotype characterization / A associação incomum entre doença de Graves, urticária crônica idiopática e insuficiência ovariana prematura: relato de caso clínico e tipagem HLA

Chronic spontaneous urticaria (CSU), defined as the occurrence of spontaneous wheals for more than six weeks, has been associated with autoimmune diseases. Herein, we report the unusual association of CSU, Graves' disease, and premature ovarian failure. Human leukocyte antigen (HLA) studies were performed. A 36-year-old woman presented symptoms and signs of hyperthyroidism for three months. In the same period, the patient complained of widespread urticarial wheals, intensely itchy, and poorly responsive to therapy with antihistaminic agents. Hyperthyroidism was confirmed biochemically, and treatment with methimazole was started. As hyperthyroidism improved, a marked improvement in her urticaria was also observed. However, the patient continued to complain of amenorrhea. Endocrine evaluation, at the age 38, was consistent with premature ovarian failure. This is the first report of coexistence of GD, CSU, and POF. The genetic background of such unusual association is a specific combination of HLA.

A urticária crônica idiopática, caracterizada pelo aparecimento de pápulas espontâneas e persistentes por pelo menos seis semanas, tem sido associada a doenças autoimunes. Apresentamos aqui o caso da associação incomum entre urticária crônica idiopática, doença de Graves e falência ovariana prematura. Foram conduzidos estudos de tipagem HLA. Uma mulher de 36 anos apresentou sinais e sintomas de hipertireoidismo por três meses. No mesmo período, a paciente queixou-se do aparecimento de pápulas urticariformes generalizadas que coçavam intensamente e não eram responsivas ao tratamento com anti-histamínicos. O hipertireoidismo foi confirmado bioquimicamente, e o tratamento com metimazol foi iniciado. Assim que os valores hormonais se normalizaram, observou-se uma melhoria significativa do quadro de urticária. No entanto, a paciente continuou a apresentar amenorreia. A avaliação endocrinológica, com a idade de 38 anos, mostrou falência ovariana prematura. Este é o primeiro caso de associação entre doença de Graves, urticária idiopática crônica e falência ovariana prematura. A base genética dessa associação incomum é representada por combinações específicas de haplótipos HLA.