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PURPOSE OF REVIEW: Maturity-onset diabetes of the young (MODY) are monogenic forms of diabetes resulting from genetic defects, usually transmitted in an autosomal dominant fashion, leading to ß-cell dysfunction. Due to the lack of homogeneous clinical features and univocal diagnostic criteria, MODY is often misdiagnosed as type 1 or type 2 diabetes, hence its diagnosis relies mostly on genetic testing. Fourteen subtypes of MODY have been described to date. Here, we review ABCC8-MODY pathophysiology, genetic and clinical features, and current therapeutic options. RECENT FINDINGS: ABCC8-MODY is caused by mutations in the adenosine triphosphate (ATP)-binding cassette transporter subfamily C member 8 (ABCC8) gene, involved in the regulation of insulin secretion. The complexity of ABCC8-MODY genetic picture is mirrored by a variety of clinical manifestations, encompassing a wide spectrum of disease severity. Such inconsistency of genotype-phenotype correlation has not been fully understood. A correct diagnosis is crucial for the choice of adequate treatment and outcome improvement. By targeting the defective gene product, sulfonylureas are the preferred medications in ABCC8-MODY, although efficacy vary substantially. We illustrate three case reports in whom a diagnosis of ABCC8-MODY was suspected after the identification of novel ABCC8 variants that turned out to be of unknown significance. We discuss that careful interpretation of genetic testing is needed even on the background of a suggestive clinical context. We highlight the need for further research to unravel ABCC8-MODY disease mechanisms, as well as to clarify the pathogenicity of identified ABCC8 variants and their influence on clinical presentation and response to therapy.
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Diabetes Mellitus Tipo 2 , Receptores de Sulfonilureias , Humanos , Receptores de Sulfonilureias/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/diagnóstico , Masculino , Feminino , Adulto , Mutação , Compostos de Sulfonilureia/uso terapêuticoRESUMO
Even though SARS-CoV-2 was declared by WHO as constituting no longer a public health emergency, the development of effective treatments against SARS-CoV-2 infection remains a critical issue to prevent complications, particularly in fragile patients. The protease inhibitor nafamostat, currently used in Japan and Korea for pancreatitis, owing to its anticoagulant properties for disseminated intravascular coagulation (DIC), is appealing for the treatment of COVID-19 infection, because it potently inhibits the transmembrane protease serine 2 (TMPRSS2) that, after virus binding to ACE-2, allows virus entry into the cells and replication. Moreover, it could prevent the DIC and pulmonary embolism frequently associated with COVID-19 infection. The goal of the RAndomized Clinical Trial Of NAfamostat (RACONA) study, designed as a prospective randomized, double-blind placebo-controlled clinical trial, was to investigate the efficacy and safety of nafamostat mesylate (0.10 mg/kg/h iv for 7 days), on top of the optimal treatment, in COVID-19 hospitalized patients. We could screen 131 patients, but due to the predefined strict inclusion and exclusion criteria, only 15 could be randomized to group 1 (n = 7) or group 2 (n = 8). The results of an ad interim safety analysis showed similar overall trends for variables evaluating renal function, coagulation, and inflammation. No adverse events, including hyperkalemia, were found to be associated with nafamostat. Thus, the RACONA study showed a good safety profile of nafamostat, suggesting that it could be usefully used in COVID-19 hospitalized patients.
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ABSTRACTRecurring and rapidly developing (flash) pulmonary edema is the hallmark of Pickering syndrome, affecting patients with hypertension and atherosclerotic renal artery stenosis (either bilateral or unilateral) in a solitary functioning kidney, and impaired renal function. We herein report on a series of consecutive patients with recurrent hospital admissions for pulmonary edema, impaired renal function (chronic kidney disease class 4-5), and atherosclerotic bilateral renal artery stenosis, in whom Pickering syndrome had been long neglected. We also describe a streamlined diagnostic strategy entailing little or no need for contrast medium, thus carrying no risks of further worsening of renal function. This allowed us to make the correct diagnosis and opened the way to revascularization by percutaneous transluminal renal angioplasty with stent, which provided swift recovery of kidney function with resolution of pulmonary congestion and long-term pulmonary edema- and dialysis-free survival in all cases. In summary, these findings support the following key messages: (1) considering the diagnosis of Pickering syndrome, followed by searching atherosclerotic renal artery stenosis, is an essential step toward a life-saving revascularization that avoids dialysis and an otherwise poor outcome; and (2) a simplified strategy entailing little or no need for contrast medium, carrying no associated risks of deteriorating renal function, permits the diagnosis of Pickering syndrome.
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Aterosclerose , Insuficiência Cardíaca , Edema Pulmonar , Obstrução da Artéria Renal , Humanos , Obstrução da Artéria Renal/complicações , Obstrução da Artéria Renal/diagnóstico por imagem , Edema Pulmonar/etiologia , Angioplastia/efeitos adversos , Artéria Renal , Aterosclerose/complicações , Síndrome , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/complicações , Stents/efeitos adversosRESUMO
Primary adrenal insufficiency (AI) due to bilateral adrenalectomy is not uncommon and causes skin hyperpigmentation, which worsens quality of life. Case description: A 50-year-old lady presented with skin hyperpigmentation after spare adrenalectomy for recurrent primary aldosteronism. In 2002 she has her first unilateral adrenalectomy and was cured at follow-up. After 16 years she developed primary aldosteronism, which was treated by spare adrenalectomy. She thereafter developed AI and started glucocorticoid replacing therapy, which did not prevent the development of full-blown skin hyperpigmentation. The addition of a low dose of dexamethasone (0.5 mg/day) to the ongoing adrenal replacement therapy normalized her plasma adrenocorticotropic hormone (ACTH) levels and regressed skin hyperpigmentation without causing Cushing-like symptoms or signs. Conclusions: This clinical case provides compelling evidence for a place for low-dose dexamethasone for regressing skin pigmentation in patients with primary AI.
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Primary aldosteronism (PA) in pregnancy (PAP) can be a serious condition and is challenging to diagnose. This study was conceived to help in the diagnosis of PAP and provide suggestions on management of PAP based on evidence retrieved using a Population, Intervention, Comparison, and Outcome search strategy. Based on the changes of aldosterone and renin occurring in normal pregnancies, we developed a nomogram that will allow to identify PAP cases. Moreover, we found that published PAP cases fell into 4 main groups differing for management and outcomes: (1) unilateral medically treated, (2) unilateral surgically treated, (3) bilateral medically treated and (4) familial forms. Results showed that complications involved 62.2% of pregnant women with nonfamilial PA and 18.5% of those with familial hyperaldosteronism type I. Adrenalectomy during pregnancy in women with PAP did not improve maternal and fetal outcomes, over medical treatment alone. Moreover, cure of maternal hypertension and mother and baby outcome were better when unilateral PA was discovered and surgically treated before or after pregnancy. Therefore, fertile women with arterial hypertension should be screened for PA before pregnancy and, if necessary, subtyped to identify unilateral forms of PA. This will allow to furnish adequate counseling, a chance for surgical cure and, therefore, for a pregnancy not complicated by aldosterone excess.
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Hiperaldosteronismo , Hipertensão , Adrenalectomia/métodos , Aldosterona , Feminino , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/cirurgia , Hipertensão/etiologia , Gravidez , Estudos RetrospectivosRESUMO
Vasoactive molecules, such as vascular endothelial growth factor (VEGF) and endothelins, share cytokine-like activities and regulate endothelial cell (EC) growth, migration, and inflammation. Some endothelial mediators and their receptors are targets for currently approved angiogenesis inhibitors, drugs that are either monoclonal antibodies raised towards VEGF, or inhibitors of vascular receptor protein kinases and signalling pathways. Pharmacological interference with the protective functions of ECs results in a similar spectrum of adverse effects. Clinically, the most common side effects of VEGF signalling pathway inhibition include an increase in arterial pressure, left ventricular dysfunction facilitating the development of heart failure, thromboembolic events including pulmonary embolism and stroke, and myocardial infarction. Sex steroids, such as androgens, progestins, and oestrogens and their receptors (ERα, ERß, GPER; PR-A, PR-B; AR) have been identified as important modifiers of angiogenesis, and sex differences have been reported for anti-angiogenic drugs. This review article discusses the current challenges clinicians are facing with regard to angiogenesis inhibitor therapy, including the need to consider sex differences affecting clinical efficacy and safety. We also propose areas for future research taking into account the role of sex hormone receptors and sex chromosomes. Development of new sex-specific drugs with improved target- and cell-type selectivity likely will open the way to personalized medicine in men and women requiring anti-angiogenic therapy to reduce adverse effects and to improve therapeutic efficacy.
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Inibidores da Angiogênese , Fator A de Crescimento do Endotélio Vascular , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Feminino , Humanos , Masculino , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Caracteres Sexuais , Resultado do Tratamento , Fatores de Crescimento do Endotélio Vascular/uso terapêuticoRESUMO
PURPOSE: Familial hyperaldosteronism type 1 (FH-1) is a rare autosomal dominant form of primary aldosteronism, which features a marked phenotypic heterogeneity, ranging from mild to severe forms of arterial hypertension that can be complicated by stroke and cardiovascular events at a young age. As affected patients usually reach the fertile age, transmission of the disease to offspring is common. Notwithstanding this, reports of FH-1 in pregnancy are limited and there is a lack of treatment guidelines. METHODS AND RESULTS: We searched the PubMed and EuropePMC databases with a PICO strategy to retrieve available information on management of FH-1 patients during pregnancy. We could identify seven relevant articles, which are herein reviewed. CONCLUSION: Based on available information on pathophysiology and treatment of FH-1 in pregnancy, recommendations for the rational management of FH-1 in pregnancy are provided.
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Hiperaldosteronismo , Hipertensão , Acidente Vascular Cerebral , Feminino , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/terapia , GravidezRESUMO
PURPOSE: Familial hyperaldosteronism type 1 (FH-1) is an autosomal dominant form of primary aldosteronism (PA), featuring a marked phenotypic heterogeneity, ranging from mild forms of PA and arterial hypertension (HT) to severe forms complicated by stroke at a young age. Affected patients usually reach the fertile age; hence, transmission of the disease to offspring is common. Notwithstanding this, only anecdotal reports of FH-1 in pregnancy exist and recommendations for treatment remain vague. MATERIALS AND METHODS AND RESULTS: We herein report on a novel FH-1 pedigree featuring very severe HT, fatal aortic dissection, and high rate of early stroke, where a young FH-1 woman was successfully managed throughout pregnancy with low-dose dexamethasone. CONCLUSIONS: Based on this experience and on available information on pathophysiology of FH-1 in pregnancy, the pros and cons of dexamethasone administration in the treatment of FH-1 in pregnancy are also discussed.
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Dexametasona/administração & dosagem , Hiperaldosteronismo/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Adulto , Feminino , Humanos , Hiperaldosteronismo/fisiopatologia , Gravidez , Complicações na Gravidez/fisiopatologiaRESUMO
The discovery of angiotensin converting enzyme-2 (ACE-2) as the receptor for SARS- CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) has implicated the renin-angiotensin-aldosterone system in acute respiratory distress syndrome (ARDS) and respiratory failure in patients with coronavirus disease-19 (COVID-19). The angiotensin converting enzyme-1-angiotensin II-angiotensin AT1 receptor pathway contributes to the pathophysiology of ARDS, whereas activation of the ACE-2-angiotensin(1-7)-angiotensin AT2 receptor and the ACE-2-angiotensin(1-7)-Mas receptor pathways have been shown to be protective. Here we propose and discuss therapeutic considerations how to increase soluble ACE-2 in plasma in order for ACE-2 to capture and thereby inactivate SARS-CoV-2. This could be achieved by administering recombinant soluble ACE-2. We also discuss why and how ACEIs and ARBs provide cardiovascular, renal and also pulmonary protection in SARS-CoV-2- associated ARDS. Discontinuing these medications in COVID-19 patients may therefore potentially be harmful.
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Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/farmacologia , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus , COVID-19 , Infecções por Coronavirus/epidemiologia , Pulmão/metabolismo , Pulmão/virologia , Pandemias , Pneumonia Viral/epidemiologia , Substâncias Protetoras/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , SARS-CoV-2RESUMO
OBJECTIVE: As metoclopramide stimulates aldosterone secretion, we tested its usefulness in the assessment of lateralization of primary aldosteronism by adrenal vein sampling (AVS). DESIGN: Prospective within-patient study in consecutive patients undergoing AVS for primary aldosteronism subtyping. METHODS: We compared the diagnostic accuracy of baseline and postmetoclopramide lateralization index and relative (to cortisol) aldosterone secretion indices (RASI) for each adrenal gland with aldosterone-producing adenoma (APA) determined by the four corners criteria as the reference diagnosis. RESULTS: We recruited 93 consecutive patients (mean age: 52 years; women 31%). Metoclopramide increased plasma aldosterone in the inferior vena cava and in both adrenal veins. The postmetoclopramide lateralization index was accurate in identifying APA, but did not increase diagnostic accuracy over baseline lateralization index, because the RASI increased similarly in both sides. Conversely, metoclopramide raised RASI to values more than 0.90 bilaterally in non-APA patients allowing accurate identification of factitious aldosterone suppression. In contrast, RASI was 0.90 or less in 48% contralateral to the tumor in APA patients. Regression analysis showed the APA patients with persistent suppression of RASI contralaterally showed a more florid primary aldosteronism phenotype. CONCLUSION: Metoclopramide does not enhance lateralization of aldosterone excess in APA, but consistently increased the value of RASI in non-APA cases, thus unmasking potentially misleading suppression of aldosterone. Postmetoclopramide RASI may therefore allow a more precise diagnosis when AVS can be achieved only unilaterally.
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Hiperaldosteronismo/diagnóstico , Metoclopramida/uso terapêutico , Aldosterona/sangue , Aldosterona/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
UNLABELLED: Vertebral osteomyelitis (or spondylodiscitis) is steadily increasing in Western countries and often results from hematogenous seeding, direct inoculation during spinal surgery, or contiguous spread from an infection in the adjacent soft tissue. We present the case of a 67-year-old white patient with type 2 diabetes who went to Hospital for high fever, back pain, and worsening of known infected ulcers in the left foot. Despite intravenous antibiotic treatment and surgical debridement of the foot infection, high fever and lower back pain continued. Bone biopsy and two consecutive blood cultures were positive for Staphylococcus aureus. A spinal magnetic resonance imaging (MRI) was performed, revealing serious osteomyelitis in L4 and L5 complicated by an epidural abscess. Contiguous or other distant focuses of infection were not identified. In this case, diabetic foot could be considered as a primary distant focus for vertebral osteomyelitis. Clinicians should consider vertebral osteomyelitis as a 'possible' diagnosis in patients with type 2 diabetes complicated by foot infection that is associated with fever and lower back pain. LEARNING POINTS: Vertebral osteomyelitis is increasing in Western countries, especially in patients with type 2 diabetes.The primary focus of infection is the genitourinary tract followed by skin, soft tissue, endocarditis, bursitis, septic arthritis, and intravascular access.Diabetic foot could be a rare primary focus of infection for vertebral osteomyelitis, and, however, vertebral osteomyelitis could be a serious, albeit rare, complication of diabetic foot.Clinicians should keep in mind the many potential complications of diabetic foot ulcerations and consider vertebral osteomyelitis as a "possible" diagnosis in patients with type 2 diabetes and foot ulcers associated with nonspecific symptoms such as lower back pain.Early diagnosis and correct management of vertebral osteomyelitis are crucial to improve clinical outcomes.
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INTRODUCTION: The prevalence of systemic arterial hypertension in young adults is increasing worldwide in association with modifiable risk factors. AIM: To assess the prevalence of high blood pressure (BP) in young adults participating to a screening campaign during the World Hypertension Day (17/05/2014), and to determine the possible association with lifestyle factors. METHODS: 493 individuals aged 18-35 years were selected in 13 Italian cities. All participants underwent BP measurement together with the administration of a questionnaire exploring: medical and drug history; traditional cardiovascular risk factors and diseases; dietary pattern; salt intake; sleep habits; mood disorders. RESULTS: High BP (≥140/90 mmHg) was found in 54 individuals, with a prevalence of 11% and awareness of 28%. Those with high BP values were more frequently men, reported a higher BMI and a greater use of corticosteroids and non-steroidal anti-inflammatory drugs, and had a lower anxiety score. Concerning dietary habits, they were more likely to eat cheese/cold cuts ≥3 times/week, to have their meals out ≥1/day and to eat in fast foods ≥1/week. In the multiple logistic regression analysis, male sex [OR 3.19, 95% CI (1.33-7.63)], BMI [OR 1.14 95% CI (1.04-1.25)], eating in fast foods [OR 3.10 95% CI (1.21-7.95)], and anxiety [OR 0.85 95% CI (0.75-0.97)], were independently associated with high BP. CONCLUSIONS: High BP values were found in 11 % young adults. Male sex, adiposity and alimentary habits were the main determinants of high BP values, indicating that young men are a suitable target for healthy lifestyle interventions.