Prolonged Hypokalemia and Delayed Diagnosis of Primary Aldosteronism: Clinical Course and Risk Factors.

INTRODUCTION: Primary Aldosteronism (PA) is a common cause of hypertension. However, diagnosis is often delayed, leading to poorer clinical outcomes. Hypokalemia with hypertension is characteristic of PA, and is an indication for screening. We evaluated if patients with PA had prolonged hypokalemia before diagnosis, the subsequent biochemical/clinical control, and factors associated with delayed diagnosis. METHODS: Our study included all PA patients with hypokalemia diagnosed between 2001 to 2022. Delayed diagnosis was defined as duration of hypokalemia of >1 year from first occurrence, to first evaluation by a PA specialist. Patients were reassessed post-adrenalectomy using the Primary Aldosteronism Surgery Outcomes criteria. We performed multivariable analysis to assess for factors associated with delayed diagnosis. RESULTS: Among 240 patients with PA who presented with hypokalemia, 122 (51%) patients had delayed diagnosis, with prolonged hypokalemia of median duration 4.5 (2.4-7.5) years. Patients with delayed diagnosis were older, had longer duration of hypertension, higher pill burden, lower renal function and more prevalent cardiovascular disease. Factors associated with delayed diagnosis included older age, presence of hyperlipidaemia, and less severe hypokalemia (serum potassium >3.0mmol/L). Compared to patients with early diagnosis, a lower proportion of those with delayed diagnosis underwent adrenal vein sampling (73% vs 58%), P<0.05. Sixty of 118 (50.8%) non-delayed, and 39 of 122 (32.0%) patients with delayed diagnosis underwent surgery. CONCLUSION: Despite manifestation of hypokalemia, many patients with PA fail to be promptly screened. Greater emphasis in hypertension guidelines, and efforts to improve awareness of PA amongst primary care physicians are urgently needed.

Expanding the use of salivary cortisol as a non-invasive outpatient test in the dynamic evaluation of suspected adrenal insufficiency.

Background: Adrenal insufficiency (AI) is potentially life-threatening, and accurate diagnosis is crucial. The first-line diagnostic test, the adrenocorticotrophic hormone (ACTH) stimulation test, measures serum total cortisol. However, this is affected in states of altered albumin or cortisol-binding globulin levels, limiting reliability. Salivary cortisol reflects free bioactive cortisol levels and is a promising alternative. However, few studies are available, and heterogenous methodologies limit applicability. Methods: This study prospectively recruited 42 outpatients undergoing evaluation for AI, excluding participants with altered cortisol-binding states. Serum (immunoassay) and salivary (liquid chromatography tandem mass spectrometry) cortisol levels were sampled at baseline, 30 min, and 60 min following 250 µg synacthen administration. AI was defined as a peak serum cortisol level <500 nmol/L in accordance with guidelines. Results: The study recruited 21 (50%) participants with AI and 21 without AI. There were no significant differences in baseline characteristics, blood pressure, or sodium levels between groups. Following synacthen stimulation, serum and salivary cortisol levels showed good correlation at all timepoints (R2 = 0.74, P < 0.001), at peak levels (R2 = 0.72, P < 0.001), and at 60 min (R2 = 0.72, P < 0.001). A salivary cortisol cut-off of 16.0 nmol/L had a sensitivity of 90.5% and a specificity of 76.2% for the diagnosis of AI. Conclusion: This study demonstrates a good correlation between serum and salivary cortisol levels during the 250 µg synacthen test. A peak salivary cortisol cut-off of 16.0 nmol/L can be used for the diagnosis of AI. It is a less invasive alternative to evaluate patients with suspected AI. Its potential utility in the diagnosis of AI in patients with altered cortisol-binding states should be further studied.

Use of testosterone replacement therapy in the rehabilitation of patients with intensive care unit-associated weakness and hospital-associated deconditioning: the Singapore General Hospital rehabilitation experience.

Introduction: Rehabilitation medicine in a tertiary care hospital involves attending to many patients affected by intensive care unit (ICU)-associated weakness (ICU-AW) and hospital-associated deconditioning (HAD). These conditions contribute to poor long-term functional outcomes and increased mortality. We explored the role of short-term adjunctive androgen therapy in this group of patients in improving the rehabilitative outcomes. Methods: This was a retrospective analysis of five patients with either ICU-AW or HAD who were given testosterone replacement therapy (TRT) or oxandrolone for a total of 2 weeks during the period from April to November 2020 was undertaken. During the 2-week trial period, the subjects underwent standard rehabilitation therapy. Results: Grip strength was used as the primary outcome measure, and the mean improvement was 4.2 kg (+24.9%), which is encouraging in a 2-week timeframe. This was matched with good functional recovery in terms of distance ambulated and less assistance needed for ambulation. Sex hormone analysis was also done before initiation of TRT, and it showed that four out of five of the subjects were biochemically hypogonadal. None of the subjects dropped out or experienced any significant adverse events over the 2-week trial period. All the subjects except one improved to full independence at 3 months post-discharge. Conclusion: TRT has the potential to be used as a useful adjunct to standard rehabilitation in enhancing functional recovery in critically ill patients. A multidisciplinary approach would ensure that suitable patients benefit from optimal nutrition, optimal rehabilitation and synergistic testosterone therapy in a clinically sound and resource-efficient fashion.

Severe and refractory hypocalcaemia secondary to osteoblastic bone metastases in bladder signet ring carcinoma: A case report and literature review.

RATIONALE: Symptomatic hypocalcaemia is uncommon, occurring in <2% of patients with malignancy. Osteoblastic bone metastasis as a cause of hypocalcaemia is rare and not reported in bladder cancer. PATIENT CONCERNS: We report a case of refractory hypocalcaemia in a patient with bladder cancer with extensive osteoblastic bone metastases. A 64-year-old male with a history of signet ring bladder carcinoma with osteoblastic bone metastases presented with severe hypocalcaemia with corrected calcium of 1.64 (2.09-2.46) mmol/L as well as hypomagnesemia and hypophosphatemia. He was previously treated with chemotherapy and immunotherapy. Denosumab was also initiated for the prevention of skeletal-related events. DIAGNOSES: Additional investigations showed significantly elevated bone formation markers N-terminal propeptide of type I procollagen and alkaline phosphatase. Chest radiography and computed tomography scan also demonstrated extensive areas of sclerotic bone lesions suggestive of osteoblastic bone metastases. He was diagnosed with severe hypocalcaemia secondary to osteoblastic bone metastases and partly to denosumab, vitamin D deficiency, and hypomagnesemia. INTERVENTIONS: He was treated aggressively with calcium and vitamin D replacement. OUTCOMES: Despite prolonged intravenous calcium replacement and high doses of oral calcium, cholecalciferol, and calcitriol replacement, he had persistent hypocalcaemia with calcium levels ranging from 1.8 to 1.9 mmol/L. He died 4 months after his admission. LESSONS: Osteoblastic bone metastases lead to an increased influx of calcium and phosphate into the bone leading to hypocalcaemia and should be considered as a differential in severe and refractory hypocalcaemia. It is rare and has not been described in bladder cancer. Precaution should be taken upon the initiation of antiresorptive in patients with osteoblastic bone metastases.

Current concepts surrounding neonatal hormone therapy for boys with congenital hypogonadotropic hypogonadism.

INTRODUCTION: Congenital hypogonadotropic hypogonadism (CHH) is a genetic disorder of reproduction and development, characterized by deficient gonadotropin-releasing hormone (GnRH) secretion or action, affecting 1-in-4,000-15,000 males. Micropenis and undescended testes are cardinal features of antenatal GnRH deficiency and could indicate absent minipuberty in the first postnatal months. In this review, we outline the pathophysiology and clinical consequences of absent minipuberty and its implications for optimal approaches to the endocrine management of affected boys. AREAS COVERED: Deficient GnRH activity during fetal development and neonatal-infancy phase of minipuberty accounts for the diminished mass of Sertoli cells and seminiferous tubules among CHH males, enduring impairment of reproductive function even during gonadotropin replacement in adult life. In overcoming this obstacle, several clinical studies of neonatal gonadotropin replacement have consistently shown positive results in inducing testicular development and correcting cryptorchidism. EXPERT OPINION: A high index of clinical suspicion, combined with hormonal testing undertaken in the postnatal period of 1-4 months, can reliably confirm or refute the diagnosis of CHH. Timely identification of CHH in affected male infants (having characteristic "red flag' developmental anomalies) opens up the possibility for gonadotropin replacement as a targeted therapy to restore the normal hormonal milieu of minipuberty. Further work is necessary in formulating optimal gonadotropin treatment regimens to be more widely adopted in clinical practice.

Re-evaluating absent clinical success after adrenalectomy in unilateral primary aldosteronism.

BACKGROUND: Adrenalectomy cures unilateral primary aldosteronism, and it improves or cures hypertension. However, a significant proportion of patients are classified with absent clinical success postsurgery, suggesting that surgery was ineffective. METHODS: We assessed all patients 6 to 12 months post-surgery for clinical outcomes using Primary Aldosteronism Surgical Outcomes (PASO), AVIS-2, and CONNsortium criteria. We estimated blood pressure changes after adjustment for changes in defined daily dosages of antihypertensive medications. We also reassessed all patients using PASO at their recent clinical visit. RESULTS: A total of 104 patients with unilateral primary aldosteronism underwent adrenalectomy at 2 tertiary centers from 2000 to 2019; 24 (23%), 31 (30%), and 54 (52%) patients were classified with absent clinical success using PASO, AVIS-2, and CONNsortium criteria, respectively. Among 24 patients with absent clinical success using PASO criteria, 10 had complete biochemical cure, 3 partial, 2 absent, and 9 had resolution of hypokalemia. On multivariable analysis, absent clinical success was associated with presence of hyperlipidemia, diabetes mellitus, and lower defined daily dosages at baseline. After adjustment for changes in defined daily dosages, 7 of 24 patients showed blood pressure improvement ≥20/10 mm Hg post-surgery. After a follow-up of mean 5.6 years, 12 of 24 patients showed partial or complete clinical success when reassessed using PASO criteria. Only 6 of 104 (5.8%) patients failed to show clinical improvement post-surgery using any of the 3 mentioned criteria or using PASO criteria at their recent clinical visit. CONCLUSION: Although some patients may be classified with absent clinical success post-surgery, the assessment of clinical outcomes remains subject to many variables. In patients with unilateral primary aldosteronism, evidenced by lateralization on AVS, unilateral adrenalectomy should remain the recommended treatment.

Recent advances in understanding and managing Kallmann syndrome.

Many of the recent advances in our understanding of human reproductive biology and its genetic basis have arisen directly via the genetic investigation of patients with Kallmann syndrome and their families. The disease is characterised by the association of an isolated defect in the secretion (or, less commonly, action) of gonadotropin-releasing hormone (GnRH) and consequent infertility, with anosmia and potentially other associated non-reproductive features. GnRH-producing neurons are located in the hypothalamic brain region after a peculiar migration during embryonic life. To date, different genes affecting GnRH neuron development/migration have so far been implicated in Kallmann syndrome, but our knowledge of the genetic basis of the syndrome remains incomplete. From a clinical point of view, the disease has suffered from a lack of definitive diagnosis and treatment, and although progress has been made in terms of timely diagnosis and evidence-based treatment of patients, implementation remains inconsistent. These aspects will be discussed in this review, which examines new strategies for arriving at more evidence-based and patient-centred medical practice in Kallmann syndrome.

Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease.

A genetic basis of congenital isolated hypogonadotropic hypogonadism (CHH) can be defined in almost 50% of cases, albeit not necessarily the complete genetic basis. Next-generation sequencing (NGS) techniques have led to the discovery of a great number of loci, each of which has illuminated our understanding of human gonadotropin-releasing hormone (GnRH) neurons, either in respect of their embryonic development or their neuroendocrine regulation as the "pilot light" of human reproduction. However, because each new gene linked to CHH only seems to underpin another small percentage of total patient cases, we are still far from achieving a comprehensive understanding of the genetic basis of CHH. Patients have generally not benefited from advances in genetics in respect of novel therapies. In most cases, even genetic counselling is limited by issues of apparent variability in expressivity and penetrance that are likely underpinned by oligogenicity in respect of known and unknown genes. Robust genotype-phenotype relationships can generally only be established for individuals who are homozygous, hemizygous or compound heterozygotes for the same gene of variant alleles that are predicted to be deleterious. While certain genes are purely associated with normosmic CHH (nCHH) some purely with the anosmic form (Kallmann syndrome-KS), other genes can be associated with both nCHH and KS-sometimes even within the same kindred. Even though the anticipated genetic overlap between CHH and constitutional delay in growth and puberty (CDGP) has not materialised, previously unanticipated genetic relationships have emerged, comprising conditions of combined (or multiple) pituitary hormone deficiency (CPHD), hypothalamic amenorrhea (HA) and CHARGE syndrome. In this review, we report the current evidence in relation to phenotype and genetic peculiarities regarding 60 genes whose loss-of-function variants can disrupt the central regulation of reproduction at many levels: impairing GnRH neurons migration, differentiation or activation; disrupting neuroendocrine control of GnRH secretion; preventing GnRH neuron migration or function and/or gonadotropin secretion and action.

Addressing bone quality and bone density after renal transplantation: A prospective evaluation of the evolution of trabecular bone score and bone mineral density over the first 5 years following renal transplantation in Asian patients.

The evolution of trabecular bone score (TBS) and bone mineral density (BMD) over the first 5 years after renal transplantation was prospectively evaluated in 164 patients. Dual energy X-ray absorptiometry (DXA) scans were performed at 0, 6, 12, 24, and 60 months. Cumulative steroid dose, serum 25(OH)D, calcium, parathyroid hormone, and total ALP levels at these time points were checked. Incident fractures were identified from X-rays/vertebral fracture assessments. Mean (SD) age, TBS, and lumbar spine BMD at baseline were 47.11 (9.53), 1.424 (0.097), and 0.935 (0.183) gm/cm2 , respectively. Baseline TBS was lower in tertiary 1.38 (0.07) vs secondary hyperparathyroidism 1.43 (0.01) vs post-parathyroidectomy 1.46 (0.11); P = .035. Trabecular bone score and BMD significantly decreased from baseline->6 months, changes after that at consecutive time points were non-significant. 11% had incident fractures during the follow-up period, majority being metatarsal with no vertebral or hip fractures noted. This first prospective evaluation of TBS and BMD evolution at multiple time points over 5 years suggest that microarchitectural and bone density deteriorations post-renal transplantation stabilize after 6 months. Stabilization of these parameters could partially account for the absence of major fractures noted in this Asian population. Possible genetic and ethnic differences in fracture risk between Asian and Caucasian renal transplant patients have to be explored through large population-based studies.

Congenital Hypogonadotrophic Hypogonadism: Minipuberty and the Case for Neonatal Diagnosis.

Congenital hypogonadotrophic hypogonadism (CHH) is a rare but important etiology of pubertal failure and infertility, resulting from impaired gonadotrophin-releasing hormone secretion or action. Despite the availability of effective hormonal therapies, the majority of men with CHH experience unsatisfactory outcomes, including chronic psychosocial and reproductive sequelae. Early detection and timely interventions are crucial to address the gaps in medical care and improve the outlook for these patients. In this paper, we review the clinical implications of missing minipuberty in CHH and therapeutic strategies that can modify the course of disease, as well as explore a targeted approach to identifying affected male infants by integrating clinical and biochemical data in the early postnatal months.

Managing congenital hypogonadotrophic hypogonadism: a contemporary approach directed at optimizing fertility and long-term outcomes in males.

Hormonal induction of spermatogenesis offers men with azoospermia due to hypogonadotrophic hypogonadism (HH) the promising prospect of fertility restoration. However, an important exception is the subset of individuals affected by congenital hypogonadotrophic hypogonadism (CHH), also known as Kallmann syndrome if associated with anosmia, who often display dismal responses to fertility induction, despite prolonged therapy. This primarily stems from the loss of minipuberty, which is a crucial phase of testicular maturation in early life that has a far-reaching impact on eventual spermatogenic capacity. Further exacerbating the compromised reproductive health is the failure to initiate timely pubertal induction in many CHH patients, resulting in suboptimal genital and psychosexual development. In this paper, the clinical implications and management of male HH across the lifespan is comprehensively reviewed, with a special focus on novel strategies that have the potential to modify disease severity and maximize fertility potential in CHH by addressing the inadequacies of conventional approaches.

A delayed diagnosis of Pallister-Hall syndrome in an adult male following the incidental detection of a hypothalamic hamartoma.

Pallister-Hall syndrome is a rare autosomal dominant condition that is associated with polydactyly and hypothalamic hamartoma and is caused predominantly by frameshift or nonsense pathogenic variants in the GLI3 gene. The majority of cases are identified during childhood; however, rare reports of diagnoses during adulthood exist. Here, we describe the identification of a novel nonsense GLI3 pathogenic variant in an adult male following the incidental detection of a hypothalamic hamartoma.

Inpatient glucose management programme in the Asian healthcare setting.

AIM: To implement an inpatient glucose management (IGM) programme in the general medical wards and evaluate its clinical efficacy. METHOD: Consecutive patients admitted to selected medical wards over a 12-month period were included in the IGM programme. All patients with ≥3 capillary blood glucose (CBG) readings (>10.0 mmol/L and/or <4.0 mmol/L) over a 24-hour period were identified electronically. A multidisciplinary team of diabetes care providers would provide specialist input to these patients. The control group comprised of consecutive patients admitted over the preceding 12 months. Outcome glucose measures include mean in-hospital glucose (MHG), mean patient-day glucose (MDG), proportion of CBG readings at predefined cut-offs and length of stay (LOS). RESULTS: Both the MHG and MDG were significantly lower following intervention (10.0±2.4 mmol/L vs 11.2±2.6 mmol/L, P<.001; 10.0±2.3 mmol/L vs 11.2±2.6 mmol/L, P<.001, respectively). Prevalence of hyperglycaemic events, defined by CBG >10.0 mmol/L, was significantly lower at 36.5% versus 51.6% (P<.001). Hypoglycaemic events of CBG <4.0 mmol/L remained infrequent at <1.0% before and after IGM programme. A greater proportion of glucose readings was controlled within the target range of 4.0-10.0 mmol/L (62.6% vs 47.6%, P<.001). With the IGM programme in place, more patients received scheduled CBG monitoring, and a significant shortening of mean LOS by 3.2 days was observed (P=.02). CONCLUSIONS: The IGM programme was effective in improving inpatient glycaemic monitoring and control in the general medical wards, with a significant reduction in LOS observed. These demonstrated the programme's potential to enhance quality and efficiency of patient care.

Clinical characteristics and outcome of thyroid storm: a case series and review of neuropsychiatric derangements in thyrotoxicosis.

OBJECTIVE: The objectives of this study were (1) to describe the presentation, demographics, and clinical course of patients admitted for thyroid storm, and (2) to identify factors associated with mortality. METHODS: A retrospective review of subjects admitted to a single academic hospital from 2006 through 2011 was conducted. Medical records for all patients who were admitted with a diagnosis of thyrotoxicosis were systematically reviewed for clinical features of thyroid storm. RESULTS: A total of 28 cases were identified. Thyroid storm was the first clinical presentation of thyrotoxicosis in 13 patients (46.4%). Noncompliance with treatment was a major trigger in previously diagnosed patients, followed by infection. The mortality rate was 25% in this series. Cardiac manifestations were predominant, with >60% of patients having severe tachycardia (heart rate >140 beats per minunte) and/or atrial fibrillation. Although central nervous system (CNS) involvement was less frequent (n = 8, 28.6%), CNS derangement of worse than mild severity was statistically associated with mortality (P = .021). There was good agreement between the Burch-Wartofsky Point Scale and Japanese Thyroid Association criteria in the diagnosis of thyroid storm in this study cohort. CONCLUSION: Thyroid storm was the first presentation of thyrotoxicosis in a significant proportion of patients, highlighting the importance of a high index of suspicion in an appropriate clinical context. The presence of neuropsychiatric manifestations appeared to portend greater risk of mortality. Prevailing evidence suggests that there are complex interactions between thyroid hormones and neurotransmitter circuits in the pathogenesis of CNS symptomology in thyrotoxicosis.