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Papers by Jana Malikova

Molecular and Cellular Endocrinology, Sep 1, 2017

Children with adrenocortical tumors (ACTs) often present with virilization due to high tumoral an... more Children with adrenocortical tumors (ACTs) often present with virilization due to high tumoral androgen production, with dihydrotestosterone (DHT) as most potent androgen. Recent work revealed two pathways for DHT biosynthesis, the classic and the backdoor pathway. Usage of alternate routes for DHT production has been reported in castration-resistant prostate cancer, CAH and PCOS. To assess whether the backdoor pathway may contribute to the virilization of pediatric ACTs, we investigated seven children suffering from androgen producing tumors using steroid profiling and immunohistochemical expression studies. All cases produced large amounts of androgens of the classic and/or backdoor pathway. Variable expression of steroid enzymes was observed in carcinomas and adenomas. We found no discriminative pattern. This suggests that enhanced androgen production in pediatric ACTs is the result of deregulated steroidogenesis through multiple steroid pathways. Thus future treatments of ACTs targeting androgen overproduction should consider these novel steroid production pathways.

Experimental Lung Research, May 28, 2015

Aim of the study: In rats, the environment with low content of oxygen induces hypoxic pulmonary h... more Aim of the study: In rats, the environment with low content of oxygen induces hypoxic pulmonary hypertension. Remodeling of pulmonary resistance arteries is particularly triggered by the mast cell degranulation products, e.g., rodent-like interstitial collagenase (matrix metalloproteinase 13). Administration of sodium cromoglycate leads to stabilization of mast cell granules, and thus to the modified remodeling process. Materials and Methods: During four-day hypoxia, we treated rats with sodium cromoglycate. Pulmonary vascular remodeling was assessed as well as counts of periarterial pulmonary mast cells, both total and matrix metalloproteinase 13-positive ones. Results: Four-day hypoxia induced remodeling of both resistance arteries and large conduit arteries. We have found increase in the tunica media thickness of resistance arteries. Tunica adventitia thickness of both resistance arteries and large conduit arteries with a diameter of over 300 μm increased as well; the latter ones revealed increase in the number of vasa vasorum in their walls. Mast cell stabilization suppressed hypoxic pulmonary vascular remodeling in resistance pulmonary arteries. Four-day hypoxia led to changes in distribution of toluidine blue-detected and MMP-13 positive periarterial mast cells; this redistribution was also influenced by the administration of sodium cromoglycate. Conclusions: The number of pulmonary periarterial mast cells seemingly decreases during hypoxia due to their degranulation, which disables their identification. Large conduit arteries do not affect final blood pressure in the pulmonary vascular bed; however, their structure changes substantially under hypoxia. Such remodeling changes are not mediated by mast cell products only since they have occurred in spite of stabilization of mast cell granules.

54th Annual ESPE, Aug 26, 2015

Hormone Research in Paediatrics, 2014

ygen species were identified in patients with unsolved FGD. Most mutations were found in the enzy... more ygen species were identified in patients with unsolved FGD. Most mutations were found in the enzyme nicotinamide nucleotide transhydrogenase, which uses the mitochondrial proton pump gradient to produce NADPH. NADPH is essential in maintaining high levels of reduced forms of antioxidant enzymes for the reduction of hydrogen peroxide. Similarly, mutations in the gene for TXNRD2 involved in this system were found in FGD patients, suggesting that the adrenal cortex is particularly susceptible to oxidative stress.

Pediatrie pro praxi, Dec 1, 2013

Vývoj hypofýzy je regulovan souhrou řady transkripcnich faktorů, ktere nejdřive řidi morfogenezi ... more Vývoj hypofýzy je regulovan souhrou řady transkripcnich faktorů, ktere nejdřive řidi morfogenezi středocarových mozkových struktur, zrakových nervů, oci a hypofýzy. Pote nasleduje diferenciace pěti specializovaných linii hypofyzarnich buněk, ktere budou celoživotně zajisťovat výrobu růstoveho hormonu, TSH, ACTH, FSH/LH a prolaktinu. U cca 25 % pacientů s vrozeným vicecetným deficitem hypofyzarnich hormonů lze v soucasne době zjistit geneticky podminěnou přicinu – nejcastěji defekt genů PROP1 nebo POU1F1, ktere koduji transkripcni faktory PROP1 a POU1F1. I když u větsiny pacientů s hypopituitarizmem geneticka diagnoza nepřinasi zasadni klinickou informaci, při defektu PROP1 je přinos vysetřeni významný. Tito pacienti mohou mit benigni hyperplazii hypofýzy připominajici tumor, který spontanně regreduje. Geneticka diagnoza je může uchranit před zbytecnou neurochirurgickou intervenci. U řady pacientů s defektem PROP1 navic postupně během života klesa sekrece ACTH. Prospektivni sledovani funkci hypofýzy tedy může předejit zavažným komplikacim z nerozpoznane centralni adrenalni insuficience.

Česko-slovenská pediatrie

Pediatrická klinika 2. lékařské fakulty Univerzity Karlovy a Fakultní nemocnice v Motole, Praha s... more Pediatrická klinika 2. lékařské fakulty Univerzity Karlovy a Fakultní nemocnice v Motole, Praha soUHRN křenek malíková J, Lebl J. Analoga GLp-1 v léčbě obezity u adolescentů. první praktické zkušenosti s podáváním liraglutidu Pro farmakoterapii obezity u adolescentů ve věku 12-17 let je od roku 2021 registrován analog GLP-1 liraglutid. Podle klinických studií přináší léčba liraglutidem redukci hmotnosti v průměru o 4,6 %. Shrnujeme první praktické zkušenosti s touto novou terapií. Od září 2021 do ledna 2023 bylo v obezitologické ambulanci Pediatrické kliniky FN Motol léčeno liraglutidem 9 chlapců. Na počátku léčby byl jejich věk 12,0 až 16,5 roku (medián 15), tělesná hmotnost 74-188 kg (medián 123) a BMI 30,7-65,9 kg/m 2 (medián 38,6). Léčba byla zahájena po neúspěchu konvenčních léčebných postupů včetně psychologické intervence. Po počáteční eskalaci dávkování byli chlapci dlouhodobě léčeni dávkou 1,8-3,0 mg denně (medián 2,4) při současné kontrole stravovacího a pohybového režimu. Během 4-15 měsíců léčby (medián 6) poklesl BMI na hodnoty 31,5-61,6 kg/m 2 (medián 35,6; p < 0,05 proti stavu před léčbou). BMI se snížil o 6,5 % (medián; rozmezí-12,7 % až +3,0 %; p < 0,05). U dvou chlapců byla léčba pro sporný efekt ukončena, u ostatních pokračuje. Výskyt nežádoucích účinků byl minimální. Po neúspěchu konvenčních postupů může liraglutid přispět ke stabilizaci nebo snížení tělesné váhy a BMI u významné části adolescentních pacientů se závažným stupněm obezity. klíčová slova: obezita, adolescence, farmakoterapie, analoga GLP-1, liraglutid sUmmARy křenek malíková J, Lebl J. GLp-1 analogues in therapy of obese adolescents. Early real-life experience with liraglutide treatment The GLP-1 analog liraglutide is registered for pharmacotherapy of obese adolescents aged 12-17 years since 2021. According to clinical studies, liraglutide administration leads to a mean weight loss 4.6%. We summarize early reallife experience with this novel therapy. Nine boys were treated with liraglutide under the supervision of outpatient clinic for obesity of Department of Pediatrics, University Hospital Motol between September 2021 and January 2023. At treatment onset, they were 12.0-16.5 years old (median 15), and had body weight 74-188 Kg (median 123) and BMI 30.7-65.9 Kg/m 2 (median 38.6). Therapy was initiated following failure of conventional treatment including psychological intervention. After the early-phase dose escalation, the long-term daily treatment dose stabilized at 1.8-3.0 mg (median 2.4). Therapy was accompanied by nutritional and behavioral intervention. Following 4-15 months on therapy (median 6), BMI declined to 31.5-61.6 Kg/m 2 (median 35.6; p<0.05 vs. treatment onset). BMI dropped by 6.5% (median; range −12.7 to +3.0%; p<0.05). Therapy was terminated in two boys due to questionable success, and is ongoing in all others. Treatment related adverse events were minimal. Liraglutide may contribute to stabilization or reduction of body weight and BMI in a significant proportion of severely obese adolescents.

Česko-slovenská pediatrie

V roce 2023 se v našem časopisu budeme soustavně věnovat epidemii dětské obezity. Pokusíme se při... more V roce 2023 se v našem časopisu budeme soustavně věnovat epidemii dětské obezity. Pokusíme se přispět k poznání jejích příčin a důsledků, ale také naznačit cesty k jejímu řešení-abychom obézním dětem a dospívajícím dokázali účinně pomoci.

Česko-slovenská pediatrie

Revised Electronic Supplemental Material for Malikova et al 2019_JCEM

Hormones, 2021

Familial non-autoimmune hyperthyroidism is a rare disease caused by germline activating variants ... more Familial non-autoimmune hyperthyroidism is a rare disease caused by germline activating variants in the thyroid-stimulating hormone receptor (TSHR) gene. The c.1856A > G (p.Asp619Gly) pathogenic variant has been described in cases of toxic adenoma but never before, to our knowledge, in a case of familial non-autoimmune hyperthyroidism. A 3-year-old boy was admitted for acute gastroenteritis presenting with goiter and tall stature. Laboratory findings revealed peripheral hyperthyroidism and negativity for thyroid autoantibodies. Antithyroid drug treatment was effective, but relapses occurred shortly after attempts to decrease the drug dose. As the boy’s father and paternal grandmother also experienced relapsing hyperthyroidism manifesting in early childhood, genetic testing of TSHR was indicated. The c.1856A > G (p.Asp619Gly) pathogenic variant was found in all three affected family members. Functional in vitro characterization of the variant verified that it enhances constitutional activation of the receptor, leading to increased production of cyclic adenosine monophosphate. Total thyroidectomy was indicated in the boy due to an unsatisfactory prognosis. Due to persistent positive thyroglobulin serum concentration, a diagnostic radioiodine scan was performed approximately 2 years later. Residual thyroid tissue was revealed; therefore, radioiodine ablative therapy was performed. Despite adequate thyroxine substitution over a long period of follow-up, TSH remained suppressed. Unlike Graves’ disease, familial non-autoimmune hyperthyroidism cases present with antithyroid drug-dependence. Not ultrasound but positive thyroglobulin serum concentration indicated residual thyroid tissue. Early detection of residual thyroid tissue and radioiodine ablation prevented the subject from experiencing relapsing hyperthyroidism and undergoing unnecessary repeated surgery. Life-long hormone substitution should be adjusted to free thyroxine rather than TSH serum concentrations.

The Lancet Diabetes & Endocrinology, 2020

BACKGROUND Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding mo... more BACKGROUND Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. INTERPRETATION Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. FUNDING Netherlands Organisation for Health Research and Development, and the Sherman Foundation.

The Journal of Clinical Endocrinology & Metabolism, 2020

Context While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause matur... more Context While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG) guidelines for variant interpretation, functional studies provide strong evidence to classify a variant as pathogenic. Objective We hypothesized that a functional evaluation can improve the interpretation of the HNF1A variants in our Czech MODY Registry. Design, Settings, and Participants We studied 17 HNF1A variants that were identified in 48 individuals (33 female/15 male) from 20 Czech families with diabetes, using bioinformatics in silico tools and functional protein analyses (transactivation, protein expression, DNA binding, and nuclear localization). Results Of the 17 variants, 12 variants (p.Lys120Glu, p.Gln130Glu, p.Arg131Pro, p.Leu139Pro, p.Met154Ile, p.Gln170Ter, p.Glu187SerfsTer40, p.Ph...

The Lancet Diabetes & Endocrinology, 2019

Background Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) cau... more Background Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T 3) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available. We aimed to investigate the effects of treatment with the T 3 analogue Triac (3,3',5-tri-iodothyroacetic acid, or tiratricol), in patients with MCT8 deficiency. Methods In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 μg Triac, the daily dose was increased progressively in 350 μg increments, with the goal of attaining serum total T 3 concentrations within the target range of 1•4-2•5 nmol/L. We assessed changes in several clinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T 3 concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T 4), and total reverse T 3 from baseline to month 12. These analyses were done in patients who received at least one dose of Triac and had at least one post-baseline evaluation of serum throid function. This trial is registered with ClinicalTrials.gov, number NCT02060474.

Hormone Research in Paediatrics, 2019

Background: The HIV drugs lopinavir and ritonavir have recently been reported to cause transient ... more Background: The HIV drugs lopinavir and ritonavir have recently been reported to cause transient adrenal insufficiency in preterm newborns. We, therefore, considered HIV drugs as a cause of transiently elevated 17-hydroxyprogesterone (17OHP) levels in a neonatal screening test for congenital adrenal hyperplasia in a preterm girl exposed to zidovudine, efavirenz, tenofovir, and emtricitabine. Objective: So far, HIV drugs have not been tested for their effect on steroidogenesis and the steroidogenic enzyme activity of CYP21A2 specifically in an in vitro system. Methods: We tested the effect of efavirenz, tenofovir, emtricitabine, and zidovudine on steroidogenesis of human adrenal H295R cells. Cells were treated with the drugs at different concentrations including concentrations in therapeutic use. The effect on CYP21A2 activity was assessed by testing the conversion of radiolabeled 17OHP to 11-deoxycortisol. Cell viability was tested by an MTT assay. In addition, recombinant human CYP...

The Journal of Steroid Biochemistry and Molecular Biology, 2017

Abiraterone is an inhibitor of CYP17A1 which is used for the treatment of castration resistant 44... more Abiraterone is an inhibitor of CYP17A1 which is used for the treatment of castration resistant 44 prostate cancer. Abiraterone is known to inhibit several drug metabolizing cytochrome P450 45 enzymes including CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and 46 CYP3A5, but its effects on steroid metabolizing P450 enzymes are not clear. In preliminary 47 results, we had observed inhibition of CYP21A2 by 1µM abiraterone. Here we are reporting 48 the effect of abiraterone on activities of CYP21A2 in human adrenal cells as well as with 49 purified recombinant CYP21A2. Cells were treated with varying concentrations of abiraterone 50 for 24 hours and CYP21A2 activity was measured using [ 3 H] 17-hydroxyprogesterone as 51 substrate. Whole steroid profile changes were determined by gas chromatography-mass 52 spectrometry. Binding of abiraterone to purified CYP21A2 protein was measured 53 spectroscopically. Computational docking was used to study the binding and interaction of 54 abiraterone with CYP21A2. Abiraterone caused significant reduction in CYP21A2 activity in 55 assays with cells and an inhibition of CYP21A2 activity was also observed in experiments 56 using recombinant purified proteins. Abiraterone binds to CYP21A2 with an estimated Kd of 57 6.3 µM. These inhibitory effects of abiraterone are at clinically used concentrations. A loss of 58 CYP21A2 activity in combination with reduction of CYP17A1 activities by abiraterone could 59 result in lower cortisol levels and may require monitoring for any potential adverse effects. 60

Molecular and cellular endocrinology, Jan 5, 2017

Children with adrenocortical tumors (ACTs) often present with virilization due to high tumoral an... more Children with adrenocortical tumors (ACTs) often present with virilization due to high tumoral androgen production, with dihydrotestosterone (DHT) as most potent androgen. Recent work revealed two pathways for DHT biosynthesis, the classic and the backdoor pathway. Usage of alternate routes for DHT production has been reported in castration-resistant prostate cancer, CAH and PCOS. To assess whether the backdoor pathway may contribute to the virilization of pediatric ACTs, we investigated seven children suffering from androgen producing tumors using steroid profiling and immunohistochemical expression studies. All cases produced large amounts of androgens of the classic and/or backdoor pathway. Variable expression of steroid enzymes was observed in carcinomas and adenomas. We found no discriminative pattern. This suggests that enhanced androgen production in pediatric ACTs is the result of deregulated steroidogenesis through multiple steroid pathways. Thus future treatments of ACTs t...

Molecular and Cellular Endocrinology, Sep 1, 2017

Children with adrenocortical tumors (ACTs) often present with virilization due to high tumoral an... more Children with adrenocortical tumors (ACTs) often present with virilization due to high tumoral androgen production, with dihydrotestosterone (DHT) as most potent androgen. Recent work revealed two pathways for DHT biosynthesis, the classic and the backdoor pathway. Usage of alternate routes for DHT production has been reported in castration-resistant prostate cancer, CAH and PCOS. To assess whether the backdoor pathway may contribute to the virilization of pediatric ACTs, we investigated seven children suffering from androgen producing tumors using steroid profiling and immunohistochemical expression studies. All cases produced large amounts of androgens of the classic and/or backdoor pathway. Variable expression of steroid enzymes was observed in carcinomas and adenomas. We found no discriminative pattern. This suggests that enhanced androgen production in pediatric ACTs is the result of deregulated steroidogenesis through multiple steroid pathways. Thus future treatments of ACTs targeting androgen overproduction should consider these novel steroid production pathways.

Experimental Lung Research, May 28, 2015

Aim of the study: In rats, the environment with low content of oxygen induces hypoxic pulmonary h... more Aim of the study: In rats, the environment with low content of oxygen induces hypoxic pulmonary hypertension. Remodeling of pulmonary resistance arteries is particularly triggered by the mast cell degranulation products, e.g., rodent-like interstitial collagenase (matrix metalloproteinase 13). Administration of sodium cromoglycate leads to stabilization of mast cell granules, and thus to the modified remodeling process. Materials and Methods: During four-day hypoxia, we treated rats with sodium cromoglycate. Pulmonary vascular remodeling was assessed as well as counts of periarterial pulmonary mast cells, both total and matrix metalloproteinase 13-positive ones. Results: Four-day hypoxia induced remodeling of both resistance arteries and large conduit arteries. We have found increase in the tunica media thickness of resistance arteries. Tunica adventitia thickness of both resistance arteries and large conduit arteries with a diameter of over 300 μm increased as well; the latter ones revealed increase in the number of vasa vasorum in their walls. Mast cell stabilization suppressed hypoxic pulmonary vascular remodeling in resistance pulmonary arteries. Four-day hypoxia led to changes in distribution of toluidine blue-detected and MMP-13 positive periarterial mast cells; this redistribution was also influenced by the administration of sodium cromoglycate. Conclusions: The number of pulmonary periarterial mast cells seemingly decreases during hypoxia due to their degranulation, which disables their identification. Large conduit arteries do not affect final blood pressure in the pulmonary vascular bed; however, their structure changes substantially under hypoxia. Such remodeling changes are not mediated by mast cell products only since they have occurred in spite of stabilization of mast cell granules.

54th Annual ESPE, Aug 26, 2015

Hormone Research in Paediatrics, 2014

ygen species were identified in patients with unsolved FGD. Most mutations were found in the enzy... more ygen species were identified in patients with unsolved FGD. Most mutations were found in the enzyme nicotinamide nucleotide transhydrogenase, which uses the mitochondrial proton pump gradient to produce NADPH. NADPH is essential in maintaining high levels of reduced forms of antioxidant enzymes for the reduction of hydrogen peroxide. Similarly, mutations in the gene for TXNRD2 involved in this system were found in FGD patients, suggesting that the adrenal cortex is particularly susceptible to oxidative stress.

Pediatrie pro praxi, Dec 1, 2013

Vývoj hypofýzy je regulovan souhrou řady transkripcnich faktorů, ktere nejdřive řidi morfogenezi ... more Vývoj hypofýzy je regulovan souhrou řady transkripcnich faktorů, ktere nejdřive řidi morfogenezi středocarových mozkových struktur, zrakových nervů, oci a hypofýzy. Pote nasleduje diferenciace pěti specializovaných linii hypofyzarnich buněk, ktere budou celoživotně zajisťovat výrobu růstoveho hormonu, TSH, ACTH, FSH/LH a prolaktinu. U cca 25 % pacientů s vrozeným vicecetným deficitem hypofyzarnich hormonů lze v soucasne době zjistit geneticky podminěnou přicinu – nejcastěji defekt genů PROP1 nebo POU1F1, ktere koduji transkripcni faktory PROP1 a POU1F1. I když u větsiny pacientů s hypopituitarizmem geneticka diagnoza nepřinasi zasadni klinickou informaci, při defektu PROP1 je přinos vysetřeni významný. Tito pacienti mohou mit benigni hyperplazii hypofýzy připominajici tumor, který spontanně regreduje. Geneticka diagnoza je může uchranit před zbytecnou neurochirurgickou intervenci. U řady pacientů s defektem PROP1 navic postupně během života klesa sekrece ACTH. Prospektivni sledovani funkci hypofýzy tedy může předejit zavažným komplikacim z nerozpoznane centralni adrenalni insuficience.

Česko-slovenská pediatrie

Pediatrická klinika 2. lékařské fakulty Univerzity Karlovy a Fakultní nemocnice v Motole, Praha s... more Pediatrická klinika 2. lékařské fakulty Univerzity Karlovy a Fakultní nemocnice v Motole, Praha soUHRN křenek malíková J, Lebl J. Analoga GLp-1 v léčbě obezity u adolescentů. první praktické zkušenosti s podáváním liraglutidu Pro farmakoterapii obezity u adolescentů ve věku 12-17 let je od roku 2021 registrován analog GLP-1 liraglutid. Podle klinických studií přináší léčba liraglutidem redukci hmotnosti v průměru o 4,6 %. Shrnujeme první praktické zkušenosti s touto novou terapií. Od září 2021 do ledna 2023 bylo v obezitologické ambulanci Pediatrické kliniky FN Motol léčeno liraglutidem 9 chlapců. Na počátku léčby byl jejich věk 12,0 až 16,5 roku (medián 15), tělesná hmotnost 74-188 kg (medián 123) a BMI 30,7-65,9 kg/m 2 (medián 38,6). Léčba byla zahájena po neúspěchu konvenčních léčebných postupů včetně psychologické intervence. Po počáteční eskalaci dávkování byli chlapci dlouhodobě léčeni dávkou 1,8-3,0 mg denně (medián 2,4) při současné kontrole stravovacího a pohybového režimu. Během 4-15 měsíců léčby (medián 6) poklesl BMI na hodnoty 31,5-61,6 kg/m 2 (medián 35,6; p < 0,05 proti stavu před léčbou). BMI se snížil o 6,5 % (medián; rozmezí-12,7 % až +3,0 %; p < 0,05). U dvou chlapců byla léčba pro sporný efekt ukončena, u ostatních pokračuje. Výskyt nežádoucích účinků byl minimální. Po neúspěchu konvenčních postupů může liraglutid přispět ke stabilizaci nebo snížení tělesné váhy a BMI u významné části adolescentních pacientů se závažným stupněm obezity. klíčová slova: obezita, adolescence, farmakoterapie, analoga GLP-1, liraglutid sUmmARy křenek malíková J, Lebl J. GLp-1 analogues in therapy of obese adolescents. Early real-life experience with liraglutide treatment The GLP-1 analog liraglutide is registered for pharmacotherapy of obese adolescents aged 12-17 years since 2021. According to clinical studies, liraglutide administration leads to a mean weight loss 4.6%. We summarize early reallife experience with this novel therapy. Nine boys were treated with liraglutide under the supervision of outpatient clinic for obesity of Department of Pediatrics, University Hospital Motol between September 2021 and January 2023. At treatment onset, they were 12.0-16.5 years old (median 15), and had body weight 74-188 Kg (median 123) and BMI 30.7-65.9 Kg/m 2 (median 38.6). Therapy was initiated following failure of conventional treatment including psychological intervention. After the early-phase dose escalation, the long-term daily treatment dose stabilized at 1.8-3.0 mg (median 2.4). Therapy was accompanied by nutritional and behavioral intervention. Following 4-15 months on therapy (median 6), BMI declined to 31.5-61.6 Kg/m 2 (median 35.6; p<0.05 vs. treatment onset). BMI dropped by 6.5% (median; range −12.7 to +3.0%; p<0.05). Therapy was terminated in two boys due to questionable success, and is ongoing in all others. Treatment related adverse events were minimal. Liraglutide may contribute to stabilization or reduction of body weight and BMI in a significant proportion of severely obese adolescents.

Česko-slovenská pediatrie

V roce 2023 se v našem časopisu budeme soustavně věnovat epidemii dětské obezity. Pokusíme se při... more V roce 2023 se v našem časopisu budeme soustavně věnovat epidemii dětské obezity. Pokusíme se přispět k poznání jejích příčin a důsledků, ale také naznačit cesty k jejímu řešení-abychom obézním dětem a dospívajícím dokázali účinně pomoci.

Česko-slovenská pediatrie

Revised Electronic Supplemental Material for Malikova et al 2019_JCEM

Hormones, 2021

Familial non-autoimmune hyperthyroidism is a rare disease caused by germline activating variants ... more Familial non-autoimmune hyperthyroidism is a rare disease caused by germline activating variants in the thyroid-stimulating hormone receptor (TSHR) gene. The c.1856A > G (p.Asp619Gly) pathogenic variant has been described in cases of toxic adenoma but never before, to our knowledge, in a case of familial non-autoimmune hyperthyroidism. A 3-year-old boy was admitted for acute gastroenteritis presenting with goiter and tall stature. Laboratory findings revealed peripheral hyperthyroidism and negativity for thyroid autoantibodies. Antithyroid drug treatment was effective, but relapses occurred shortly after attempts to decrease the drug dose. As the boy’s father and paternal grandmother also experienced relapsing hyperthyroidism manifesting in early childhood, genetic testing of TSHR was indicated. The c.1856A > G (p.Asp619Gly) pathogenic variant was found in all three affected family members. Functional in vitro characterization of the variant verified that it enhances constitutional activation of the receptor, leading to increased production of cyclic adenosine monophosphate. Total thyroidectomy was indicated in the boy due to an unsatisfactory prognosis. Due to persistent positive thyroglobulin serum concentration, a diagnostic radioiodine scan was performed approximately 2 years later. Residual thyroid tissue was revealed; therefore, radioiodine ablative therapy was performed. Despite adequate thyroxine substitution over a long period of follow-up, TSH remained suppressed. Unlike Graves’ disease, familial non-autoimmune hyperthyroidism cases present with antithyroid drug-dependence. Not ultrasound but positive thyroglobulin serum concentration indicated residual thyroid tissue. Early detection of residual thyroid tissue and radioiodine ablation prevented the subject from experiencing relapsing hyperthyroidism and undergoing unnecessary repeated surgery. Life-long hormone substitution should be adjusted to free thyroxine rather than TSH serum concentrations.

The Lancet Diabetes & Endocrinology, 2020

BACKGROUND Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding mo... more BACKGROUND Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. INTERPRETATION Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. FUNDING Netherlands Organisation for Health Research and Development, and the Sherman Foundation.

The Journal of Clinical Endocrinology & Metabolism, 2020

Context While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause matur... more Context While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG) guidelines for variant interpretation, functional studies provide strong evidence to classify a variant as pathogenic. Objective We hypothesized that a functional evaluation can improve the interpretation of the HNF1A variants in our Czech MODY Registry. Design, Settings, and Participants We studied 17 HNF1A variants that were identified in 48 individuals (33 female/15 male) from 20 Czech families with diabetes, using bioinformatics in silico tools and functional protein analyses (transactivation, protein expression, DNA binding, and nuclear localization). Results Of the 17 variants, 12 variants (p.Lys120Glu, p.Gln130Glu, p.Arg131Pro, p.Leu139Pro, p.Met154Ile, p.Gln170Ter, p.Glu187SerfsTer40, p.Ph...

The Lancet Diabetes & Endocrinology, 2019

Background Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) cau... more Background Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T 3) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available. We aimed to investigate the effects of treatment with the T 3 analogue Triac (3,3',5-tri-iodothyroacetic acid, or tiratricol), in patients with MCT8 deficiency. Methods In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 μg Triac, the daily dose was increased progressively in 350 μg increments, with the goal of attaining serum total T 3 concentrations within the target range of 1•4-2•5 nmol/L. We assessed changes in several clinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T 3 concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T 4), and total reverse T 3 from baseline to month 12. These analyses were done in patients who received at least one dose of Triac and had at least one post-baseline evaluation of serum throid function. This trial is registered with ClinicalTrials.gov, number NCT02060474.

Hormone Research in Paediatrics, 2019

Background: The HIV drugs lopinavir and ritonavir have recently been reported to cause transient ... more Background: The HIV drugs lopinavir and ritonavir have recently been reported to cause transient adrenal insufficiency in preterm newborns. We, therefore, considered HIV drugs as a cause of transiently elevated 17-hydroxyprogesterone (17OHP) levels in a neonatal screening test for congenital adrenal hyperplasia in a preterm girl exposed to zidovudine, efavirenz, tenofovir, and emtricitabine. Objective: So far, HIV drugs have not been tested for their effect on steroidogenesis and the steroidogenic enzyme activity of CYP21A2 specifically in an in vitro system. Methods: We tested the effect of efavirenz, tenofovir, emtricitabine, and zidovudine on steroidogenesis of human adrenal H295R cells. Cells were treated with the drugs at different concentrations including concentrations in therapeutic use. The effect on CYP21A2 activity was assessed by testing the conversion of radiolabeled 17OHP to 11-deoxycortisol. Cell viability was tested by an MTT assay. In addition, recombinant human CYP...

The Journal of Steroid Biochemistry and Molecular Biology, 2017

Abiraterone is an inhibitor of CYP17A1 which is used for the treatment of castration resistant 44... more Abiraterone is an inhibitor of CYP17A1 which is used for the treatment of castration resistant 44 prostate cancer. Abiraterone is known to inhibit several drug metabolizing cytochrome P450 45 enzymes including CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and 46 CYP3A5, but its effects on steroid metabolizing P450 enzymes are not clear. In preliminary 47 results, we had observed inhibition of CYP21A2 by 1µM abiraterone. Here we are reporting 48 the effect of abiraterone on activities of CYP21A2 in human adrenal cells as well as with 49 purified recombinant CYP21A2. Cells were treated with varying concentrations of abiraterone 50 for 24 hours and CYP21A2 activity was measured using [ 3 H] 17-hydroxyprogesterone as 51 substrate. Whole steroid profile changes were determined by gas chromatography-mass 52 spectrometry. Binding of abiraterone to purified CYP21A2 protein was measured 53 spectroscopically. Computational docking was used to study the binding and interaction of 54 abiraterone with CYP21A2. Abiraterone caused significant reduction in CYP21A2 activity in 55 assays with cells and an inhibition of CYP21A2 activity was also observed in experiments 56 using recombinant purified proteins. Abiraterone binds to CYP21A2 with an estimated Kd of 57 6.3 µM. These inhibitory effects of abiraterone are at clinically used concentrations. A loss of 58 CYP21A2 activity in combination with reduction of CYP17A1 activities by abiraterone could 59 result in lower cortisol levels and may require monitoring for any potential adverse effects. 60

Molecular and cellular endocrinology, Jan 5, 2017

Children with adrenocortical tumors (ACTs) often present with virilization due to high tumoral an... more Children with adrenocortical tumors (ACTs) often present with virilization due to high tumoral androgen production, with dihydrotestosterone (DHT) as most potent androgen. Recent work revealed two pathways for DHT biosynthesis, the classic and the backdoor pathway. Usage of alternate routes for DHT production has been reported in castration-resistant prostate cancer, CAH and PCOS. To assess whether the backdoor pathway may contribute to the virilization of pediatric ACTs, we investigated seven children suffering from androgen producing tumors using steroid profiling and immunohistochemical expression studies. All cases produced large amounts of androgens of the classic and/or backdoor pathway. Variable expression of steroid enzymes was observed in carcinomas and adenomas. We found no discriminative pattern. This suggests that enhanced androgen production in pediatric ACTs is the result of deregulated steroidogenesis through multiple steroid pathways. Thus future treatments of ACTs t...