Combination of spironolactone and DPP-4 inhibitors for treatment of SARS-CoV-2 infection: a literature review.

Coronavirus disease 2019 (COVID-19) is still causing hospitalization and death, and vaccination appears to become less effective with each emerging variant. Spike, non-spike, and other possible unrecognized mutations have reduced the efficacy of recommended therapeutic approaches, including monoclonal antibodies, plasma transfusion, and antivirals. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) and probably dipeptidyl peptidase 4 (DPP-4) to initiate the process of endocytosis by employing host proteases such as transmembrane serine protease-2 (TMPRSS-2) and ADAM metallopeptidase domain 17 (ADAM17). Spironolactone reduces the amount of soluble ACE2 and antagonizes TMPRSS-2 and ADAM17. DPP-4 inhibitors play immunomodulatory roles and may block viral entry. The efficacy of treatment with a combination of spironolactone and DPP-4 inhibitors does not appear to be affected by viral mutations. Therefore, the combination of spironolactone and DPP-4 inhibitors might improve the clinical outcome for COVID-19 patients by decreasing the efficiency of SARS-CoV-2 entry into cells and providing better anti-inflammatory, antiproliferative, and antifibrotic effects than those achieved using current therapeutic approaches such as antivirals and monoclonal antibodies.

Metainflammation in COVID-19.

A new coronavirus pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been on the rise. This virus is fatal for broad groups of populations, including elderly, men, and patients with comorbidities among which obesity is a possible risk factor. The pathophysiologic connections between obesity/metainflammation and COVID-19 may be directly related to increasing soluble ACE2 (angiotensin-converting enzyme 2) levels which potentiate the viral entrance into the host cells, or indirectly related to dysregulation of immune system, microvascular injury and hypercoagulability. The SARS-CoV-2 S-glycoprotein interacts mainly with ACE2 or possibly DPP4 receptors to enter into the host cells. The host proteases, especially TMPRSS2 (transmembrane protease serine 2), support the fusion process and virus entry. While membranous ACE2 is considered a port of entry to the cell for SARSCoV- 2, it seems that soluble ACE2 retains its virus binding capability and enhances its entry into the cells. Interestingly, ACE2 on cell membrane may have protective roles by diminishing cytokine storm-related injuries to the organs. Applying medications that can reduce soluble ACE2 levels, antagonizing TMPRSS2 or blocking DPP4 can improve the outcomes of COVID-19. Metformin and statins through immunomodulatory activities, Orlistat by reducing viral replication, and thiazolidinediones by upregulating ACE2 expression have potential beneficial effects against COVID-19. However, the combination of dipeptidyl peptidase-4 (DPP4) inhibitors and spironolactone/ eplerenone seems to be more effective by reducing soluble ACE2 level, antagonizing TMPRSS2, maintaining ACE2 on cell membrane and reducing risk of viral entry into the cells.

Oncogenic osteomalacia secondary to glomus tumor.

SUMMARY: Oncogenic osteomalacia secondary to glomus tumor is extremely rare. Localization of causative tumors is critical as surgical resection can lead to a complete biochemical and clinical cure. We present a case of oncogenic osteomalacia treated with resection of glomus tumor. A 39-year-old woman with a history of chronic sinusitis presented with chronic body ache and muscle weakness. Biochemical evaluation revealed elevated alkaline phosphatase hypophosphatemia, increased urinary phosphate excretion, low calcitriol, and FGF23 was unsuppressed suggestive of oncogenic osteomalacia. Diagnostic studies showed increase uptake in multiple bones. Localization with MRI of paranasal sinuses revealed a sinonasal mass with concurrent uptake in the same area on the octreotide scan. Surgical resection of the sinonasal mass was consistent with the glomus tumor. The patient improved both clinically and biochemically postoperatively. Along with the case of oncogenic osteomalacia secondary to a glomus tumor, we have also discussed in detail the recent development in the diagnosis and management of oncogenic osteomalacia. LEARNING POINTS: Tumor-induced osteomalacia is a rare cause of osteomalacia caused by the secretion of FGF23 from mesenchymal tumors. Mesenchymal tumors causing TIO are often difficult to localize and treat. Resection of the tumor can result in complete resolution of biochemical and clinical manifestations in a very short span of time. Glomus tumor can lead to tumor induced osteomalacia and should be surgically treated.

Adrenal Vein Cortisol to Metanephrine Ratio for Localizing ACTH-Independent Cortisol-Producing Adenoma: A Case Report.

CONTEXT: Finding the source of adrenocorticotropic hormone (ACTH)-independent cortisol-producing adenoma in the patients with subclinical Cushing syndrome (SCS) and bilateral adrenal nodules is sometimes challenging. Computed tomography (CT) and positron emission tomography are helpful, but adrenal venous sampling (AVS) is the gold standard approach. However, interpretation of AVS is important to improve the accuracy of decision-making for surgery. We report a case and review of the literature to assess the benefit of using adrenal vein cortisol to metanephrine ratio to determine the source of cortisol production in SCS and bilateral nodules. EVIDENCE ACQUISITION: Three authors searched PubMed for data on patients with SCS who had AVS procedure and measurements of cortisol and catecholamines. CASE DESCRIPTION: A 51-year-old woman with SCS and hypertension crisis presented to our clinic. Paraclinical investigations revealed that she had an ACTH-independent cortisol-producing adenoma and her CT scan showed bilateral adrenal nodules. After AVS, cortisol (high to low) lateralization ratio could not determine the source of cortisol production but the cortisol to metanephrine ratio localized the source to the left side, which included the larger nodule according to CT measurements. Left adrenalectomy led to clinical and paraclinical improvement. CONCLUSION: There is a possibility of co-secretion of other steroids accompanied with cortisol in the setting of ACTH-independent SCS. Moreover, cortisol measurement alone and interpretation of AVS results based on cortisol values may not help lateralizing the source of cortisol production with bilateral adrenal nodules. Therefore, we suggest applying cortisol to metanephrine ratio with the same gradient (gradient > 2.3, highest to lowest concentration) when the source of cortisol production cannot be determined by cortisol lateralization ratio.

Delivery of Euthyroid Baby following Hyperthyroidism in Twin Gestation with Coexisting Complete Hydatidiform Mole.

CONTEXT: Gestational trophoblastic disease (GTD) is a rare complication of pregnancy, ranging from molar pregnancy to choriocarcinoma. Twin pregnancies with GTD and coexisting normal fetus are extremely rare with an estimated incidence of 1 case per 22,000-100,000 pregnancies. Molecular mimicry between human chorionic gonadotrophin (hCG) and thyroid-stimulating hormone (TSH) leads to gestational trophoblastic hyperthyroidism (GTH) which is further associated with increased maternal and fetal complications. This is the first reported case in literature describing the delivery of a baby with biochemical euthyroid status following a twin pregnancy with hydatidiform mole (HM) associated with gestational trophoblastic hyperthyroidism (GTH). CASE DESCRIPTION: A 24-year-old G4 P3 Caucasian female with twin gestation was admitted to hospital for gestation trophoblastic hyperthyroidism. She was later diagnosed to have twin pregnancy with complete mole and coexisting normal fetus complicated by gestational trophoblastic hyperthyroidism (GTH). Despite the risk associated with the continuation of molar pregnancy, per patient request, pregnancy was continued till viability of the fetus. The patient underwent cesarean section due to worsening preeclampsia and delivered a euthyroid baby at the 24th week of gestation. CONCLUSIONS: Twin pregnancy with gestational trophoblastic disease and coexisting normal fetus is associated with high risk of hyperthyroidism, and careful monitoring of the thyroid function test along with dose titration of thionamides is of utmost importance throughout the gestation. If normal thyroid hormone levels are maintained during the pregnancy, euthyroidism could be successfully achieved in the baby.

Endocrine manifestations of systemic mastocytosis in bone.

Systemic Mastocytosis (SM) is characterized by accumulation of clonal, neoplastic proliferations of abnormal mast cells (MC) in one or more organ system other than skin. Presence of these multifocal clusters of abnormal mast cells is an essential feature of SM. Frequently associated with D816V (KIT) mutation, the presence of this mutation and elevated serum tryptase are minor criteria for diagnosis. SM manifestations depend on the degree of mast cell proliferation, activation and degranulation. SM has a variable prognosis and presentation, from indolent to "smoldering" to life-threatening disease. Bone manifestations of SM include: osteopenia with or without lytic lesions, osteoporosis with or without atraumatic fracture, osteosclerosis with increased bone density, and isolated lytic lesions. Male sex, older age, higher bone resorption markers, lower DKK1 level, lower BMD, absence of urticaria pigmentosa, and alcohol intake are all associated with increased risk of fracture. Treatment of SM is generally palliative. Most therapy is symptom-directed; and, infrequently, chemotherapy for refractory symptoms is indicated. Anti-histamines may alleviate direct bone effects of histamine. Bisphosphonates, including alendronate, clodronate, pamidronate and zoledronic acid are recommended as a first line treatment of SM and osteoporosis. Interferon α may act synergistically with bisphosphonates. As elevation of RANKL and OPG is reported in SM, denosumab could be an effective therapy for bone manifestations of SM.

Adiponectin as a Protective Factor Against the Progression Toward Type 2 Diabetes Mellitus in Postmenopausal Women.

Serum adiponectin levels have been suggested to be predictors of type 2 diabetes mellitus in diverse populations. However, the relationship between circulating adiponectin levels and the risk of development of type 2 diabetes in postmenopausal women has not been investigated.A total of 382 healthy postmenopausal women who participated in a prospective cohort study were followed for 5.8 years. Type 2 diabetes mellitus was defined according to the criteria set out by the American Diabetes Association. Adiponectin, osteoprotegerin (OPG), and high-sensitivity C-reactive protein (hs-CRP) levels were measured using ELISA.Of 195 women who did not have diabetes at baseline and who were reexamined in the second phase of the study for diabetic status, 35 subjects (17.9%) developed type 2 diabetes mellitus during the 5.8 years follow-up period. The women with type 2 diabetes had lower adiponectin levels than the healthy postmenopausal women. Multiple regression analysis showed that, after adjustments were made for age, cardiovascular risk factors, OPG, and hs-CRP levels, higher baseline adiponectin levels were associated with a lower relative risk (RR) of having type 2 (RR = 0.07, confidence interval [CI]: 0.01-0.66, P = 0.021).Higher baseline adiponectin levels functioned as a predictor of a lower risk of developing type 2 diabetes mellitus among postmenopausal women during a 5.8 years follow-up study. Therefore, it is suggested that elevated adiponectin levels may offer protection against the development of type 2 diabetes mellitus after the menopause.

Treatment of iron-deficiency anemia in patients with subclinical hypothyroidism.

OBJECTIVE: Subclinical hypothyroidism is a health state that is associated with hypercholesterolemia, infertility, iron-deficiency anemia, and poor obstetric outcome. This article summarizes the results of a prospective clinical investigation of whether treatment of subclinical hypothyroidism and iron-deficiency anemia with a combination of levothyroxine plus iron salt would be superior to each treatment alone. METHODS: In a randomized, double-blind, active-controlled trial, 60 patients with subclinical hypothyroidism and iron-deficiency anemia received iron salt+placebo (20 patients), levothyroxine+placebo (20 patients), or levothyroxine+iron salt (20 patients) for 3 months. Change from baseline (before) to end of study (after) in hemoglobin, ferritin, and thyroid-stimulating hormone levels were compared among groups. RESULTS: The increase from baseline in hemoglobin and ferritin in the levothyroxine+iron group was superior to the other groups, in which a decrease in thyroid-stimulating hormone in the 2 groups that received levothyroxine was superior to the group treated with iron salt. CONCLUSION: Subclinical hypothyroidism was investigated in iron-deficient patients with no acceptable response to iron salt alone. A combination of levothyroxine and iron salt is better than each one alone.

Pioglitazone reduces central obesity in polycystic ovary syndrome women.

OBJECTIVE: Based on the role of polycystic ovary syndrome as a cause of metabolic syndrome with chronic anovulation, obesity, hyperinsulinemia and hyperandrogenism, development of effective treatment for its obesity is a priority. MATERIALS/METHODS: We designed a study, involving 52 patients of 19-36 years of age, to test the pioglitazone in women with polycystic ovary syndrome. Subjects were assigned to receive pioglitazone for 3 months. Body mass index, waist circumference and hip circumference were measured before and after 3 months of pioglitazone prescription. RESULTS: Fifty patients completed the study. No complication reported during the study period. Waist circumference, hip circumference and waist to height ratio decreased significantly. Body weight and body mass index increased. No significant improvement was seen in acne, acanthosis, hirsutism and menstrual irregularities. CONCLUSION: Pioglitazone has beneficial effects on central obesity of the patients with polycystic ovary syndrome but other clinical consequences of the syndrome may not improve with the drug.