Contemporary Medical Management of Primary Hyperparathyroidism:A Systematic Review

IntroductionPrimary hyperparathyroidism is increasingly an asymptomatic disease at diagnosis, but the recognized guidelines for management are based on evidence obtained from studies on patients with symptomatic disease, and surgery is not always indicated. Other patients are unable to undergo surgery, and thus a medical treatment is warranted. This systematic review provides an overview of the existing literature on contemporary pharmaceutical options available for the medical management of primary hyperparathyroidism.MethodsDatabases of medical literature were searched for articles including terms for primary hyperparathyroidism and each of the included drugs. Data on s-calcium, s-parathyroid hormone, bone turnover markers, bone mineral density (BMD) and hard endpoints were extracted and tabulated, and level of evidence was determined. Changes in s-calcium were estimated and a meta-regression analysis was performed.ResultsThe 1,999 articles were screened for eligibility and 54 were included in the review. Weighted mean changes calculated for each drug in s-total calcium (mean change from baseline ± SEM) were pamidronate (0.31 ± 0.034 mmol/l); alendronate (0.07 ± 0.05 mmol/l); clodronate (0.20 ± 0.040 mmol/l); mixed bisphosphonates (0.16 ± 0.049 mmol/l); and cinacalcet (0.37 ± 0.013 mmol/l). The meta-analysis revealed a significant decrease of effect on s-calcium with time for the bisphosphonates (Coef. −0.049 ± 0.023, p = 0.035), while cinacalcet proved to maintain its effect on s-calcium over time. Bisphosphonates improved BMD while cinacalcet had no effect.DiscussionThe included studies demonstrate advantages and drawbacks of the available pharmaceutical options that can prove helpful in the clinical setting. The great variation in how primary hyperparathyroidism is manifested requires that management should rely on an individual evaluation when counseling patients. Combining resorptive agents with calcimimetics could prove rewarding, but more studies are warranted

Associations between trabecular bone score and biochemistry in surgically vs conservatively treated outpatients with primary hyperparathyroidism:A retrospective cohort study

Purpose: Trabecular Bone Score (TBS) is a software-based method for indirect assessment of trabecular bone structure of the spine, based on analysis of pixels in dual energy x-ray absorptiometry (DXA) images. Few studies describe the use of TBS in patients with primary hyperparathyroidism (PHPT). This study aimed at further describing this relationship, investigating possible correlations between biochemistry, body mass index (BMI), fracture incidence and TBS. Methods: Cross-sectional study of 195 patients with verified PHPT, surgically (27) or conservatively (168) treated at the Department of Endocrinology, Aalborg University Hospital. TBS was acquired by reanalyzing DXA-images of the included subjects from the outpatient clinic. Biochemical variables were obtained from clinical routine blood samples taken in relation to the DXA-scans. History of fractures and medical history was obtained from radiology reports and medical charts. Results: Patients with active PHPT had a TBS-score signifying a partly degraded bone structure, whereas surgically treated patients had a normal bone structure as judged by TBS, though the difference in TBS-score was not statistically significant. Use of antiresorptive treatment was negatively associated with BMD but not TBS. No correlations between the biochemical variables and TBS were found. A negative correlation between TBS and BMI in patients with PHPT was present. Patients experiencing a fragility fracture had a significantly lowered TBS, BMD and T-Score. Conclusion: Biochemistry does not seem to predict bone status in terms of TBS in patients with PHPT. TBS is negatively correlated to BMI, which is also seen in patients not suffering from PHPT. The lack of a predictive value for antiresorptive treatment for TBS may raise concern. TBS appears to have a predictive value when assessing risk of fracture in patients with PHPT. Mini abstract: This cross-sectional study investigates possible correlations between biochemical variables, body mass index (BMI) and trabecular bone score (TBS) in 195 patients with primary hyperparathyroidism. It finds no correlation between biochemical variables and TBS, but finds a negative correlation between TBS and BMI and a clear association between fracture incidence and low TBS-score. Keywords: Primary hyperparathyroidism, Trabecular bone score, Body mass index, Osteoporosis, Osteopenia, Biochemical variable

Preproghrelin gene, ghrelin receptor and metabolic syndrome

Otyłość prosta to zespół wielogenowy, którego ekspresja jest modulowana nie tylko przez czynniki środowiskowe, ale przede wszystkim przez liczbę oddziałujących na siebie zmodyfikowanych genów. Wśród genów kandydatów związanych z występowaniem fenotypu otyłości jest gen greliny. Grelina odgrywa istotną rolę w regulacji przyjmowania pożywienia i jest najsilniejszym z dotychczas poznanych stymulatorów wydzielania hormonu wzrostu (GH, growth hormone). Działa poprzez receptor dla substancji mających zdolność uwalniania GH (GHSR1a, growth hormone secretagogue receptor type 1a). Mutacje w obrębie genu preprogreliny, greliny lub jej receptora mogą odpowiadać za małe stężenia greliny w osoczu otyłych. Dwie spośród zidentyfikowanych mutacji: Arg51Gln i Leu72Met, najczęściej opisywane, zmieniają sekwencję aminokwasową cząsteczki greliny (Arg51Gln) i preprogreliny (Leu72Met). Mimo że nie znaleziono bezpośredniej korelacji między obecnością mutacji Arg51Gln a fenotypem otyłości, to u nosicieli tej mutacji wykazano znamiennie mniejsze stężenia greliny. Stwierdzono również, że nosiciele allelu 51Gln znacznie częściej chorują na cukrzycę typu 2 i nadciśnienie tętnicze. Okazało się, że nosicielstwo allelu Met72 wiąże się z większymi stężeniami insulinopodobnego czynnika wzrostu 1(IGF-1, insulin-like growth factor-1) w surowicy, zapobiega akumulacji tłuszczu oraz rozwojowi sercowo-naczyniowych powikłań u otyłych. Obecność nieprawidłowości genetycznych w obrębie genów warunkujących aktywność greliny może odpowiadać za upośledzone wydzielanie GH w trzewnym typie otyłości i rozwój zespołu metabolicznego u pewnej liczby otyłych. Natomiast niektóre mutacje w obrębie genu preprogreliny mogą chronić pewien odsetek otyłych osób przed rozwojem tego zespołu.Obesity is a multi-gene syndrome, expression of which is modulated not only by environmental factors but above all by a number of modificated genes interacting with each other. Among candidate genes related to obesity phenotype is ghrelin gene. Ghrelin plays a significant role in feeding regulation and is the strongest stimulator of growth hormone (GH) secretion. Ghrelin acts by GH secretagogue receptor type 1a (GHSR1a). Mutations in preproghrelin and ghrelin gene, or ghrelin receptor gene could be responsible for low ghrelin levels observed in obese individuals. Among identificated mutations, two Arg51Gln and Leu72Met are most often described and change amino-acid sequence of ghrelin (Arg51Gln) and preproghrelin (Leu72Met). Although no direct relationship between Arg51Gln mutation and obesity phenotype was found, it had been shown that carriers of Arg51Gln mutation had significantly decreased plasma ghrelin levels. Furthermore 51Gln allele carriers had higher prevalence of type 2 diabetes mellitus and hypertension than non-carriers. Met 72 carrier status is associated with higher serum insulin-like growth factor-1 (IGF-1) levels and seems to be a protective factor against fat accumulation and cardiovascular complications of obesity. No evidence of relationship between ghrelin receptor gene polymorphisms and body mass regulation was found, however, until now there is no study on relationships between these polymorphisms and metabolic complications of obesity. The presence of genetic variants in ghrelin or GHSR gene could be responsible for impaired GH secretion in visceral type obesity and development of metabolic syndrome in some of obese subjects. On the other hand, some mutations in preproghrelin gene could be protective against metabolic syndrome

Induction of puberty with human chorionic gonadotropin (hCG) followed by reversal of hypogonadotropic hypogonadism in Kallmann syndrome

Introduction: Kallmann syndrome (KS) is a rare, congenital disorder combining hypogonadotropic hypogonadism (HH) due to GnRH-deficiency with anosmia. Traditionally thought to require lifelong therapy it turns out to be a reversible condition in some patients. Case report: We present a case of a 22-year old man with absent puberty due to KS, in whom genetic testing revealed heterozygosity for a mutation in the PROK2 gene. Pubertal development and virilisation was achieved by using human chorionic gonadotropin (hCG) injections followed by testosterone replacement. During the follow-up we observed reversal of hypogonadism allowing discontinuation of testosterone treatment. Normalisation of testicular volume as well as gonadotropin and inhibin B levels through a 2-year postreversal period was seen. Conclusions: Treatment with hCG is effective in inducing pubertal development and may have advantage over testosterone replacement due to a potential of gonadal maturation. A regular assessment of testicular volume and biochemical surveillance including measuring of serum inhibin B and gonadotropins are necessary for a timely detection of reversal of GnRH deficiency.Wstęp: Zespół Kallmanna jest rzadkim, wrodzonym zaburzeniem łączącym hipogonadyzm hipogonadotropowy spowodowany niedobo­rem GnRH z anosmią. Tradycyjnie uważany za wymagający leczenia przez całe życie u części pacjentów okazuje się stanem odwracalnym. Opis przypadku: Prezentujemy przypadek 22-letniego mężczyzny z brakiem cech pokwitania z powodu zespołu Kallmanna, u którego badanie genetyczne ujawniło heterozygotyczność dla mutacji genu PROK2. Rozwój cech pokwitania i wirylizacji osiągnięto, podając in­iekcje ludzkiej gonadotropiny kosmówkowej (hCG), a stosując następnie leczenie testosteronem. Podczas obserwacji wystąpiło zjawisko samoistnego ustąpienia hipogonadyzmu hipogonadotropowego (tzw. reversal), co pozwoliło na przerwanie leczenia testosteronem. W ciągu następnych 2 lat stwierdzono normalizację wielkości jąder, a także stężeń gonadotropin i inhibiny B. Wnioski: Leczenie hCG jest skuteczne w indukcji pokwitania i może mieć przewagę nad leczeniem testosteronem z uwagi na możliwość procesu dojrzewania jąder. Częsta ocena wielkości jąder i kontrola parametrów biochemicznych, takich jak stężenie gonadotropin i inhi­biny B, są konieczne dla wczesnego wykrycia zjawiska reversal

Ocena jakości życia u pacjentów z chorobą Gravesa-Basedowa i postępującą naciekową oftalmopatią tarczycową w trakcie skojarzonego leczenia metyloprednizolonem i radioterapią przestrzeni pozagałkowych

Wstęp: Celem pracy była ocena jakości życia u chorych z naciekową postacią oftalmopatii tarczycowej (GO, Graves’ opthalmopathy) w trakcie pulsacyjnego leczenia metylprednizolonem w połączeniu z radioterapią oczodołów oraz próba odniesienia wyników leczenia oftalamopatii do zmian w jakości życia. Materiał i metody: Badaniem objęto grupę 29 pacjentów w wieku 25-74 lat (śr. wieku: 52 ± 6 lat) z naciekową GO. Podstawą kwalifikacji chorych do leczenia oftalmopatii było uzyskanie eutyreozy, postępujący charakter zmian ocznych, stopień zaawansowania zmian ocznych oceniany w oparciu o klasyfikację NO SPECS mieszczący się przynajmniej w klasie 3c, indeks oftalmopatii według Donaldson ≥ 4 punktów. Za aktywną postać GO przyjmowano wartości klinicznego wskaźnika aktywności (CAS, clinical activity score) ≥ 4. Podczas leczenia, u chorych zastosowano 6 cykli soli sodowej metyloprednizolonu w dawce 1,0 g/dobę podczas jednogodzinnych wlewów dożylnych, przez kolejne trzy dni w tygodniu. Między 2. a 4. cyklem Solu-Medrolu prowadzono radioterapię tkanek pozagałkowych promieniami X o energii 10 MeV. Grupę kontrolną utworzono ze zdrowych ochotników, dobranych w stosunku do grupy badanej pod względem płci, wieku, posiadanego wykształcenia i uzależnienia od nikotyny. Składała się ona z 53 osób, w wieku 21-75 lat (śr. wieku: 52,4 ± 14 lat). Badania jakości życia przeprowadzano, opierając się na kwestionariuszu MOS SF-36. Wyniki: Pacjenci z GO gorzej oceniali jakość życia w stosunku do osób zdrowych w zakresie ogólnej sprawności, ograniczeń fizycznych i emocjonalnych w pełnieniu funkcji, stanu zdrowia, witalności, funkcjonowania społecznego, zdrowia psychicznego oraz występowania i nasilenia bólu. Nie wykazano korelacji pomiędzy jakością życia a wiekiem, płcią, czasem trwania choroby Gravesa-Basedowa i oftalmopatii. Podobnie nie stwierdzono zależności pomiędzy aktywnością i zaawansowaniem klinicznym zmian ocznych a jakością życia. Zastosowanie skojarzonej terapii GO spowodowało znamienne zmniejszenie stopnia zaawansowania zmian ocznych i obniżenie aktywności choroby. Po leczeniu pacjenci wskazali na poprawę jakości życia w zakresie ograniczeń fizycznych w odgrywaniu ról, występowania i nasilenia bólu oraz witalności. Pozostałe parametry jakości życia nie różniły się istotnie statystycznie. Wnioski: Oftalamopatia tarczycowa powoduje znaczne pogorszenie jakości życia. Stopień zaawansowania klinicznego i aktywność oftalmopatii nie wykazują związku z jakością życia. Skuteczności leczenia oftalmopatii nie można oceniać, kierując się zmianami w jakości życia pacjentów.Introduction: The aim of the study was to assess quality of life (QoL) in patients with infiltrative form of Graves’ ophthalmopathy (GO) during the combined pulse treatment with methylprednisolone and orbital radiotherapy, and also to search for the relation between the results of ophthalmopathy treatment and changes in QoL. Material and methods: The study involved 29 patients aged 25-74 (the mean age: 52 ± 6 years) with infiltrative form of GO. They were classified for ophthalmopathy treatment on the basis of the following factors: the obtained euthyreosis, progressive character of eye changes, the level of eye changes determined on the basis of NO SPECS classification (at least class 3c), ophthalmopathy index (OI) according to Donaldson ≥ 4. GO was diagnosed as active if CAS (clinical activity score) ≥ 4. During the treatment, the patients received 6 cycles of methylprednisolone sodium succinate in doses of 1,0 g/24 h given as one-hour-long intravenous infusions for three successive days in a week. Between the 2nd and 4th cycle of Solu-Medrol, orbital radiotherapy with 10 MeV X-rays was performed. The control group was made up of healthy volunteers selected with regard to sex, age, educational background and nicotine addiction so as they corresponded with the study group. It involved 53 individuals aged 21-75 (the mean age: 52,4 ± 14 years). QoL was assessed by means of the MOS SF-36 questionnaire. Results: Patients with GO evaluated their QoL lower than healthy individuals, which referred to physical functioning, physical and emotional role functioning, general health, vitality, social functioning, mental health and bodily pain. No correlation was found between quality of life and such factors as age, sex, or duration time of Graves disease and ophthalmopathy. Analogically, no relation was observed between the activity and stage of clinical development of eye changes and QoL. The use of the combined GO therapy contributed to a considerable decrease in the development of eye changes and the disease activity. After treatment, the patients’ QoL improved which referred to physical role functioning, bodily pain, and vitality. Other QoL parameters did not statistically significantly differ. Conclusions: GO causes a considerable worsening of QoL. The stage of clinical development and activity of GO find no reflection in QoL. Effectiveness of treatment for GO cannot be evaluated on the basis of changes in QoL

Contemporary Medical Management of Primary Hyperparathyroidism:A Systematic Review

IntroductionPrimary hyperparathyroidism is increasingly an asymptomatic disease at diagnosis, but the recognized guidelines for management are based on evidence obtained from studies on patients with symptomatic disease, and surgery is not always indicated. Other patients are unable to undergo surgery, and thus a medical treatment is warranted. This systematic review provides an overview of the existing literature on contemporary pharmaceutical options available for the medical management of primary hyperparathyroidism.MethodsDatabases of medical literature were searched for articles including terms for primary hyperparathyroidism and each of the included drugs. Data on s-calcium, s-parathyroid hormone, bone turnover markers, bone mineral density (BMD) and hard endpoints were extracted and tabulated, and level of evidence was determined. Changes in s-calcium were estimated and a meta-regression analysis was performed.ResultsThe 1,999 articles were screened for eligibility and 54 were included in the review. Weighted mean changes calculated for each drug in s-total calcium (mean change from baseline ± SEM) were pamidronate (0.31 ± 0.034 mmol/l); alendronate (0.07 ± 0.05 mmol/l); clodronate (0.20 ± 0.040 mmol/l); mixed bisphosphonates (0.16 ± 0.049 mmol/l); and cinacalcet (0.37 ± 0.013 mmol/l). The meta-analysis revealed a significant decrease of effect on s-calcium with time for the bisphosphonates (Coef. −0.049 ± 0.023, p = 0.035), while cinacalcet proved to maintain its effect on s-calcium over time. Bisphosphonates improved BMD while cinacalcet had no effect.DiscussionThe included studies demonstrate advantages and drawbacks of the available pharmaceutical options that can prove helpful in the clinical setting. The great variation in how primary hyperparathyroidism is manifested requires that management should rely on an individual evaluation when counseling patients. Combining resorptive agents with calcimimetics could prove rewarding, but more studies are warranted

Maternal and fetal outcomes in phaeochromocytoma and pregnancy:a multicentre retrospective cohort study and systematic review of literature

Background Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy.Methods We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases. The inclusion criteria were pregnancy after 1980 and PPGL before or during pregnancy or within 12 months post partum. Eligible patients from the retrospective study and systematic review were included in the analysis. Outcomes of interest were maternal or fetal death and maternal severe cardiovascular complications of catecholamine excess. Potential variables associated with these outcomes were evaluated by logistic regression.Findings The systematic review identified seven studies (reporting on 63 pregnancies in 55 patients) that met the eligibility criteria and were of adequate quality. A further 197 pregnancies in 186 patients were identified in the International Pheochromocytoma and Pregnancy Registry. After excluding 11 pregnancies due to potential overlap, the final cohort included 249 pregnancies in 232 patients with PPGL. The diagnosis of PPGL was made before pregnancy in 37 (15%) pregnancies, during pregnancy in 134 (54%), and after delivery in 78 (31%). Of 144 patients evaluated for genetic predisposition for phaeochromocytoma, 95 (66%) were positive. Unrecognised PPGL during pregnancy (odds ratio 27.0; 95% CI 3.5-3473.1), abdominal or pelvic tumour location (11.3; 1.5-1440.5), and catecholamine excess at least ten-times the upper limit of the normal range (4.7; 1.8-13.8) were associated with adverse outcomes. For patients diagnosed during pregnancy, alpha-adrenergic blockade therapy was associated with fewer adverse outcomes (3.6; 1.1-13.2 for no alpha-adrenergic blockade vs alpha-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0.9; 0.3-3.9 for no surgery vs surgery).Interpretation Unrecognised and untreated PPGL was associated with a substantially higher risk of either maternal or fetal complications. Appropriate case detection and counselling for premenopausal women at risk for PPGL could prevent adverse pregnancy-related outcomes. Copyright (C) 2020 Elsevier Ltd. All rights reserved