This opinion article focusses on treatment targets in adults with early treated PKU (etPKU), specifically the recommended phenylalanine (Phe) level. The current body of evidence on the relationship between Phe levels at different times in life and neurocognitive functioning and quality of life in adults with etPKU is summarized and discussed. Based on this, recommendations on metabolic control throughout adult life are made. Maintaining plasma Phe < 600 umol/L up to (at least) age 20 years may be advisable. There is however a lack of robust evidence to support a specific single phenylalanine target level that is applicable to all adults and, in later adulthood, a patient-centred approach to optimize nutritional status and achieve individualised treatment goals should be taken. The available evidence indicates reduced processing speed and attentional difficulties with higher Phe concentrations in only a proportion of adult patients. These are potentially reversible with lowering of Phe levels. Patients may wish to achieve lower phenylalanine levels because they experience better mood or cognitive functioning, and the levels where they perceive these benefits are variable (e.g. <600, < 800 or < 1000 umol/L). Equally, patients may wish to avoid potential, as yet undiscovered, long term negative consequences of higher levels. All patients wishing to lower their Phe levels should receive full support to reach their goals. In some cases, subjective symptoms are the reason patients want to reduce their Phe levels. In such cases, subjective symptoms should be clearly defined and quantified, and the relationship between their occurrence and phenylalanine level, as well as improvement with lower phenylalanine levels, should be clearly established before treatment is intensified. Patients who, after having received and understood all currently available evidence on outcomes, do not wish to lower their Phe levels, should not be pressed to do so. In order to further understand the correlation between Phe levels at the different stages of life and neurological and cognitive functioning of etPKU patients a large, independent, multicentre registry needs to be established. This is urgently needed to facilitate rational treatment of PKU in adulthood, preventing both over- and undertreatment and facilitating cost-effective use of new and currently available drugs.

Introduction : Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism, which can be successfully treated by natural protein restricted diet with Phe-free protein substitution. The long-term effects of the early-treated PKU (ETPKU) on cardiovascular (CV) health have been in the focus of research. Methods : We have assessed traditional and non-traditional CV risk factors of 104 ETPKU patients. Our intention was to compare patients’ traditional CV risk factors to those of matched non-PKU controls. After dividing the group of ETPKU patients into two based on a mean Phe level of 600 μmol/L as cut-off, we have observed the differences in CV risk between patients with optimal and suboptimal therapy adherence, in both sexes. Results : According to our findings, PKU patients had a significantly higher BMI (p=0.0249), but a better lipid profile (p<0.01). Women with PKU had a higher prevalence of diabetes and hypertension compared to controls. Female ETPKU patients with optimal therapy adherence had significantly more favourable BMI, skeletal muscle mass, creatine kinase, uric acid, folic acid and vitamin B12 levels than female ETPKU patients with suboptimal therapy adherence. Among male ETPKU patients, the difference between patients with optimal and suboptimal therapy adherence was significant in case of uric acid, homocysteine, ankle-brachial index, folic acid and vitamin B12. About one third of the studied patients presented with a higher-than-normal ankle-brachial index. Conclusion : There is a growing number of identified CV risk factors in patients living with PKU, which makes the facilitation of early CV screening necessary.

A significant number of patients with primary hypothyroidism report persistent symptoms and decreased quality of life (QoL) despite biochemically adequate levothyroxine replacement. Individual variations in thyroxine conversion, autoimmune inflammation, and psychological factors have all been implicated as a potential cause. In this cross-sectional study we have examined the association of numerous demographic, disease-specific, and laboratory parameters as well as three patient reported outcome measures with thyroid-dependent QoL as measured by the Underactive Thyroid-Dependent Quality of Life Questionnaire. Patients were stringently selected to minimize the confounding effect of comorbidities or inadequate hormone replacement. We used validated questionnaires to assess somatosensory amplification, depression, and symptom number. Determinants of QoL were evaluated using uni- and multivariable linear modeling, and mediation analysis. Our final sample consisted of 157 patients. 70.7

Introduction: In phenylketonuria (PKU), toxic phenylalanine (Phe) can harm other organs beyond the brain. Furthermore, the lifelong therapy of PKU consists of consumption of increased amounts of amino-acid mixture that provoke hyperfiltration in the glomeruli. Therefore, the adherence to therapy in PKU might influence the long-term kidney function in PKU patients. Methods: Data from 41 adult, early treated PKU patients were analyzed in this 10-year, retrospective, monocentric study. Two subgroups were created according to their therapy adherence: one with long-term blood Phe levels in the therapeutic range (<600 µmol/L), and one with suboptimal blood Phe levels. Renal function and metabolic parameters were collected over 10 years. Kidney function parameters were compared between the two groups and associations between blood Phe levels and kidney function were tested. Results: After 10 years, serum creatinine levels (p = 0.369) and estimated glomerular filtration rate (eGFR) (p = 0.723) did not change significantly from baseline in the good therapeutic group. The suboptimal therapeutic group’s eGFR decreased in the same period (from 110.4 ± 14 mL/min/1.73 m2 to 94.2 ± 16 mL/min/1.73 m2, p = 0.017). At 10 years, the suboptimal therapeutic group had an increased serum creatinine level (81 ± 14.4 μmol/L vs. 71.5 ± 13 μmol/L, p = 0.038), and a decreased eGFR (94.2 ± 16 mL/min/1.73 m2 vs. 103.3 ± 13 mL/min/1.73 m2p = 0.031) compared to the good adhering group. Significant negative correlation between Phe levels and eGFR (r = −0.41, p = 0.008) was observed. Conclusion: Long-term suboptimal therapy adherence in PKU patients with high blood Phe levels may lead to deterioration in kidney function.

Objective:The mainstay therapy of hypothyroidism is levothyroxine (LT4). In most cases lifelong treatment is warranted, therefore, choosing adequate doses are of paramount significance. The purpose of this study was to assess several factors that have been proposed to influence LT4 therapy including etiology of hypothyroidism, gender, age, bodyweight, BMI, concomitant drug use, disease severity and time since diagnosis in patients with stable, adequately controlled hypothyroidism. Methods:In this cross-sectional study we analysed past medical history, anthropometric data and biochemical parameters reflecting thyroid function of patients with chronic hypothyroidism who were adequately treated (TSH levels in normal range) with LT4 for at least 6 months. Potential predictors of LT4 requirement were evaluated using uni- and multivariate linear modelling. Results:191 individuals were enrolled in this study, who were divided into autoimmune (n = 147) and post-surgery (n = 44) groups. Mean age, time since diagnosis and LT4 dose (1.3 versus 1.1 mcg/kgBW) were significantly lower in the autoimmune group. In the post-surgery group age was the only significant (p = 0.016) predictor of LT4 dose. In the autoimmune group BMI (p = 0.001), time since diagnosis (p = 0.023), as well as their interaction (p = 0.012) turned out to be significant predictors of LT4 requirement. Conclusions:Our results implicate the necessity of differentiating between etiologies of hypothyroidism when starting or changing thyroxine replacement therapy. Patient in both groups required significantly lower doses of LT4 replacement, than previous reports suggest, to maintain stable euthyroidism. Distinctly different factors predicted hormone requirement in the two study groups.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

An increasing number of women with urea cycle disorders (UCDs) are reaching child-bearing age and becoming pregnant. Improved diagnostics and increased awareness of inherited metabolic diseases has also led to more previously undetected women being diagnosed with a UCD during or shortly after pregnancy. Pregnancy increases the risk of acute metabolic decompensation with hyperammonemia-which can occur in any trimester, and/or the postpartum period, and may lead to encephalopathy, psychosis, coma, and even death, if not diagnosed promptly and treated appropriately. There are also (theoretical) concerns that a maternal UCD, or its treatment, may cause potential risks for the unborn child. Currently evidence on management and outcome of pregnancies in UCDs is limited to case reports and there are no clear guidelines. In order to inform management and investigate outcomes of pregnancies in women with a UCD, we performed a retrospective review of published cases and analyzed data collected from an international online survey. We conclude that, although risk during the intra- and postpartum period exists, multidisciplinary management by an experienced team and a prospective plan usually result in successful pregnancy, labor, delivery, and postpartum period. No deaths were reported in mothers managed accordingly. With the exception of male neonates with Ornithine Transcarbamylase deficiency, the clinical outcome of children born to mothers with UCDs appears positive, although follow-up is limited. The outcome for women presenting with a first acute metabolic decompensation during pregnancy or postpartum is less favorable. Deaths were associated with diagnostic delay/late management of hyperammonemia in previously undiagnosed women.

Background Phenylketonuria (PKU) is a rare inborn error of metabolism affecting the catabolism of phenylalanine (Phe). To date, findings regarding health-related quality of life (HRQoL) in adults with early-treated classical PKU are discrepant. Moreover, little is known about metabolic, demographic, and cognitive factors associated with HRQoL. Hence, we aimed to investigate HRQoL and its association with demographic, metabolic, and cognitive characteristics in a large European sample of adults with early-treated classical PKU. Results This cross-sectional study included 124 adults with early-treated classical PKU from Hungary, Italy, Spain, Switzerland, and Turkey. All participants prospectively completed the PKU quality of life questionnaire (PKU-QoL), a questionnaire specifically designed to evaluate the impact of PKU and its treatment on HRQoL in individuals with PKU. In addition, information about Phe levels (concurrent and past year), demographic (age and sex), and cognitive variables (intelligence quotient, IQ) were collected. Most domains revealed little or no impact of PKU on HRQoL and more than three-quarters of the patients rated their health status as good, very good, or excellent. Nevertheless, some areas of concern for patients were identified. Patients were worried about the guilt that they experience if they do not adhere to the dietary protein restriction and they were most concerned about high Phe levels during pregnancy. Further, tiredness was the most affected symptom, and the supplements’ taste was considered a main issue for individuals with PKU. The overall impact of PKU on HRQoL was higher in women ( U = 1315.5, p = .012) and in adults with a lower IQ ( r s = − 0.448, p = .005). The overall impact of dietary protein restriction was higher in adults with higher concurrent Phe levels ( r s = 0.272, p = .007) and higher Phe levels during the past year ( r s = 0.280, p = .009). Conclusion The impact of PKU on most domains assessed in the PKU-QoL was considered to be low. These results likely reflect the successful implementation of the newborn screening resulting in the prevention of severe adverse long-term outcomes. However, a particular clinical focus should be given to patients with lower IQ, higher Phe levels, and women, as these variables were associated with a lower HRQoL.

Objectives:This study aimed to characterise the clinicopathological features and prognostic factors of a large cohort of Hungarian patients with adrenocortical cancer diagnosed between 2000-2021.Patients and methods:This retrospective study included seventy-four patients (27 men and 47 women) with histologically confirmed adrenocortical cancer in a single tertiary referral endocrine centre. Descriptive statistics were performed, providing summaries of selected clinical and pathological parameters. Clinicopathological factors contributing to overall survival were analysed.Results:The median age of patients was 48,5 years (17-84 years) at diagnosis. The majority of cases were diagnosed at ENSAT stage II (39,2%) and stage IV (33,8%). At diagnosis, the median tumour size was 9,0 cm (4,5-20 cm). In 47 patients (71,6%), the tumour was hormonally active. The median overall survival and the 5-year survival rate were 23,5 months (95% CI, 17-30,5 months) and 18,3%, respectively. Primary tumour resection was performed in 68 patients (91,8%); R0 surgical resection was achieved in 30 patients. In univariate Cox regression model, tumours with stages III and IV, high proliferative activity (Ki67-index > 10%), R1-R2 surgical resection state and hormonal activity were associated with poorer survival. Cortisol excess, both isolated and combined with androgen production, was associated with poorer survival. Fifty-five patients were treated with mitotane. The overall survival of patients achieving therapeutic mitotane plasma concentration was significantly better compared to those who never reached it [27.0 (2-175) months vs 18.0 (2-83) months; p<0.05)]. The median age, the distribution of gender, ENSAT stage, resection state and Ki67-index did not differ between these two groups. The time needed to reach the therapeutic range of serum mitotane was 96.5 days (95% CI, 75-133 days).Conclusion:Our results confirm previous data that disease stage, mitotic activity, the resection state and the mitotane treatment achieving therapeutic concentration are the most critical parameters influencing the prognosis of adrenocortical cancer. Our data suggest that hormonal activity may be more frequent than described previously, and it is a strong and independent prognostic factor of overall survival. To our knowledge, this is the first single-centre study confirming the prognostic importance of achieving therapeutic mitotane concentration.

Introduction: Patients with phenylketonuria (PKU) must follow a lifelong phenylalanine (Phe)-restricted diet with additional amino acid supplementations, and this may put them at risk for nutritional disturbances. However, the body composition and nutritional status of adult patients with PKU has only been partially explored. The current study aims to assess the body composition of adult patients with PKU using multifrequency bioimpedance analysis (MF-BIA) and to reveal potential correlations between therapy adherence and body composition. Additionally, we compared body composition of patients with healthy controls. Methods: Fifty adult patients with early-treated PKU (27 female and 23 male) and 40 healthy, age- and gender-matched controls were included in this single-center, cross-sectional study. MF-BIA was performed on all subjects. Additionally, we determined serum nutritional markers for all patients. In the PKU patient group, correlation analyses were performed between body composition parameters and therapy adherence. We compared body composition of patients with PKU and controls using BIA. Results: The proportion of overweight was 56% among all patients with PKU. Female patients with PKU had significantly higher body fat percentage compared with controls. In parallel with higher fat content, we observed lower muscle mass, protein, and mineral content among female patients with PKU compared to controls. Such findings were not observed in male patients. Female patients with PKU had decreased therapy adherence and had significantly lower prealbumin levels compared with males. There was no significant correlation observed between body composition parameters and therapy adherence over the last 10 years in the PKU patient group. Conclusion: Although female patients had less optimal therapy adherence over the last 10 years compared with male patients, our results suggest that this does not influence body composition fundamentally. Our results suggest that obesity is an important comorbidity in young adult patients with PKU, especially in females. We advocate that nutritional assessments and weight management should be additional objectives of PKU management to provide optimal care.

Mitotane has been used for the treatment of adrenocortical cancer (ACC) for over 50 years. Despite its widespread use both in monotherapy and in combination with chemotherapeutics, our knowledge of its mechanism of action and therapeutic efficacy is scarce. The number of patients with advanced ACC who have achieved complete remission documented by detailed clinical data is below ten. We report a case of a 64-year-old woman with a non-functional ACC. Histological examination showed vascular invasion, Ki67 of 10% and a mitotic count of 3/10 high-power field. Immunohistochemistry revealed p53 positivity. Pathological TNM grade was reported as T2N0M0, ENSAT stage 2. Nine months after the initial diagnosis, re-staging CT revealed multiple peritoneal nodules, lymph node and kidney metastases confirmed by histologic examination. Mitotane monotherapy was started with a maintenance dose between 2.0 and 2.5 grams/day. Partial remission was established at six months. Subsequently, for another 12 months, each of the three-monthly CT scans confirmed complete remission. Nineteen months after the initiation of mitotane, an unexpected sudden death occurred. A detailed autopsy work-up, performed in the full awareness of oncological history, confirmed complete remission. The authors review the molecular biomarkers and clinical features reported as predictors of response to mitotane monotherapy.

Purpose: Macular structure is poorly evaluated in early-treated phenylketonuria (ETPKU). To evaluate potential changes, we aimed to examine retinas of PKU patients using optical coherence tomography (OCT) with additional OCT angiography (OCTA) and compare the results to healthy controls.& nbsp; Methods: A total of 100 adults were recruited in this monocentric, case-control study: 50 patients with ETPKU (mean age: 30.66 +/- 8.00 years) and 50 healthy controls (mean age: 30.45 +/- 7.18 years). Macular thickness, vessel density and flow area of the right eye was assessed with spectral domain OCT angiography SD-OCT(A). Macular microstructural data between the ETPKU and control group was compared. In the ETPKU group, the relationship between visual functional parameters (best corrected visual acuity [VA], spherical equivalent [SE], contrast sensitivity [CS] and near stereoacuity) and microstructural alterations was examined. The dependency of OCT(A) values on serum phenylalanine (Phe) level was analysed.& nbsp; Results: There was significant average parafoveal and perifoveal total retinal layer thinning in ETPKU patients compared to healthy controls (p < 0.016 and p < 0.001, respectively), while the foveal region remained unchanged in the ETPKU group. Whole macular and parafoveal superficial capillary plexus density was significantly decreased in ETPKU compared to controls (p < 0.001). There were no significant differences in the foveal avascular zone, nonflow area, macular superficial and deep capillary plexus between the groups. The temporal parafoveal inner retinal layer thickness was found to negatively correlate with individual Phe levels (r = -0.35, p = 0.042). There was no difference in vascular density and retinal thickness in the subgroup analysis of patients with good therapy adherence compared to patients on a relaxed diet.& nbsp; Conclusions: Durable elevation in Phe levels are only partially associated with macular retinal structural changes. However, therapy adherence might not influence these ophthalmological complications.

There is very limited experience regarding the interventional radiological treatment of adrenocortical cancer (ACC). We present the case of a 57-year-old female patient with a large, potentially unresectable left-sided ACC and two hepatic metastases. Both liver tumors were effectively treated by trans-arterial embolization (TAE), followed by TAE of the bulky primary tumor as a life-saving intervention necessitated by severe intratumoral bleeding. Surgical removal of the primary tumor revealed complete necrosis. The patient is considered tumor free after 3.5 years. To the best of our knowledge, this is the first report to show that even a primary ACC may be completely ablated by selective embolization, and the fourth to prove the curative potential of liver TAE for ACC metastases. This case highlights the potential of selective embolization in ACC treatment.

INTRODUCTION:Benign thyroid nodules are frequent findings in imaging studies, most of the time not requiring any intervention. Treatment is usually started when nodules increase in size, the patient becomes symptomatic or clinically relevant hyperthyroidism develops. Thermoablation is an effective alternative modality. In Hungary, our team has pioneered these interventions using radiofrequency ablation for decreasing the size of the nodules.AIM:We are presenting our results showing the effectiveness of this treatment after introducing the role, importance and technique of thermoablation in benign thyroid nodules.METHOD:Between June of 2016 and September of 2019, 186 nodules of 140 patients were treated with radiofrequency ablation and had at least 6 months of follow up. The volume and diameter of all the ablated nodules were measured and calculated, then the decreases of these parameters were followed using ultrasonography. The mean follow-up time was 12.5 ± 5.9 months.RESULTS:The size measurements at the follow-up ultrasonography examinations showed a decrease in size and vascularity. The mean volume reduction was 44.7 ± 17.6% at one-month post-treatment and 72.9 ± 17.9% at 6 months. There were 3 minor complications.CONCLUSIONS:Radiofrequency ablation represents a feasible, effective, well tolerated method for outpatient treatment of benign thyroid nodules. This method is a valuable alternative to surgical treatments in selected cases. Orv Hetil. 2020; 161(27): 1131-1136.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Purpose Defective function of phenylalanine hydroxylase in phenylketonuria (PKU) results in the accumulation of phenylalanine (Phe) and the reduction of tyrosine (Tyr) in the blood, interfering in the normal development and function of organs and tissues in the body. Tyr is the precursor of catecholamines, secreted in response to stress by the adrenal medulla and paraganglia. The aim of this study was to evaluate plasma catecholamine and amino acid response to an escalating series of sympathetic stress tests in PKU patients. Methods Twelve males with classical PKU (aged 18–41 years) and ten healthy male controls were included in this study. The subjects were exposed to three different sympathetic stress stimulations: cold pressor, isometric handgrip, and peak treadmill tests to exhaustion. Physiological, metabolic, and hormonal changes were determined. Results Aerobic capacity (VO 2max ) was significantly lower in the PKU group ( p = 0.018); however, relative VO 2max was similar in the two groups during the spiroergometric test. No significant differences in norepinephrine or in epinephrine response were found between the two groups during the different stimulation tests. Blood Phe increased significantly in the PKU group compared with controls ( p = 0.027) during the spiroergometric test, while Tyr levels remained stable in both groups. Conclusion PKU itself might not influence stress-induced catecholamine changes. Only strenuous exercise increased blood Phe levels in PKU subjects.