Secondary Polycythemia and Non-Islet Cell Tumor-induced Hypoglycemia in Advanced Hepatocellular Carcinoma: A Case Report.

Continuously holding its position as the sixth most common cause of cancer and the third leading cause of cancer death, globally, Hepatocellular Carcinoma (HCC) remains as a healthcare priority. Production of various substances may result into systemic or metabolic complications, often known as paraneoplastic phenomena of HCC. A 56-year-old male with history of untreated chronic hepatitis B arrived with generalized weakness and intermittent headache in the last two days prior to admission. Laboratory findings demonstrated elevated hemoglobin (20.5 g/dl), alpha-fetoprotein (29,845 ng/dl), and d-Dimer (2,120 ng/ml) levels. Hypoglycemia (44 mg/dl) was documented with normal basal insulin level, confirming non-islet cell tumor hypoglycemia. Abdominal multiphasic CT-scan demonstrated a large solid lesion involving the whole right liver lobe, hyper-enhanced at arterial phase and wash-out pattern at venous and delayed phases, with portal vein thrombosis; thus, confirming HCC BCLC C. Further examinations revealed hypercellularity from bone marrow biopsy with the absence of JAK2 mutation. He underwent serial phlebotomy and received 80 mg acetylsalicylic acid orally, as well as cytoreductive agent to reduce the risk of thrombosis. Despite applications of different interventions, control of hypoglycemia could not be achieved without parenteral administration of high dextrose load. He was planned to receive oral multikinase inhibitor, however, he passed away due to severe hospital-acquired pneumonia. Paraneoplastic phenomena are common in HCC. Increased risk of blood hyper-viscosity and thrombosis attributed to polycythemia, as well as medical emergency resulting from hypoglycemia showed that both conditions should not be overlooked since they may worsen the patient's prognosis.

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The male patient, one day old, was admitted to the hospital due to hypoglycemia accompanied by apnea appearing six hours after birth. The patient had transient hypoglycemia early after birth, and acute heart failure suddenly occurred on the eighth day after birth. Laboratory tests showed significantly reduced levels of adrenocorticotropic hormone and cortisol, and pituitary magnetic resonance imaging was normal. Genetic testing results showed that the patient had probably pathogenic compound heterozygous mutations of the TBX19 gene (c.917-2A>G+c.608C>T), inherited respectively from the parents. The patient was conclusively diagnosed with congenital isolated adrenocorticotropic hormone deficiency caused by mutation of the TBX19 gene. Upon initiating hydrocortisone replacement therapy, cardiac function rapidly returned to normal. After being discharged, the patient continued with the hydrocortisone replacement therapy. By the 18-month follow-up, the patient was growing and developing well. In neonates, unexplained acute heart failure requires caution for possible endocrine hereditary metabolic diseases, and timely cortisol testing and genetic testing should be conducted.

Pathogenic Potential of a PCK1 Gene Variant in Cytosolic PEPCK Deficiency: A Compelling Case Study.

BACKGROUND Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency is an extremely rare autosomal recessive inherited error of metabolism in which gluconeogenesis is impaired, resulting in life-threatening episodes of hypoglycemia and metabolic acidosis. The diagnosis of gluconeogenesis disorders is challenging. In the diagnostic pathway, the molecular test plays a paramount role. CASE REPORT The aim of the paper is to present the case report of a girl with recurrent episodes of severe hypoglycemia, in whom molecular diagnosis enabled the confirmation of PEPCK - C deficiency. The patient experienced 4 episodes of severe hypoglycemia. Most of them were accompanied by hyperlacticaemia, metabolic acidosis, and elevated liver enzymes. All of the metabolic decompensations were triggered by infectious agents. The episodes resolved after continuous infusion of high-dose glucose. Due to the recurrent character of the disease, a genetic condition was suspected. The differential diagnosis included metabolic and endocrinological causes of hypoglycemia. Two variants in the PCK1 gene were detected: c.265G>A p.(Glu89Lys) in exon 3 and c.925G>A p.(Gly309Arg) in exon 6. As c.925G>A p.(Gly309Arg) is a known pathogenic variant, the second variant was first described in June 2023 in the ClinVar database and described as "with unknown clinical significance". CONCLUSIONS According to the clinical symptoms observed in the presented case, the variant c.265G>A p.(Glu89Lys) in PCK1 gene should be considered likely pathogenic. We suggest considering molecular diagnostics in every patient presented with recurrent, severe hypoglycemia with accompanying liver damage as most accurate, feasible, and reliable method.

Management of Outpatients With Diabetes at High Risk of Hypoglycemia.

This JAMA Clinical Guidelines Synopsis summarizes the Endocrine Society's 2023 recommendations on management of outpatients with diabetes and high risk of hypoglycemia.

Relationships of hypoglycemia awareness, hypoglycemia beliefs, and continuous glucose monitoring glycemic profiles with anxiety and depression symptoms in adults with type 1 diabetes using continuous glucose monitoring systems.

AIMS: To evaluate relationships of hypoglycemia awareness, hypoglycemia beliefs, and continuous glucose monitoring (CGM) glycemic profiles with anxiety and depression symptoms in adults with type 1 diabetes (T1D) who use CGM. METHODS: A cross-sectional survey and data collections were completed with 196 T1D adults who used CGM (59% also used automated insulin delivery devices (AIDs)). We assessed hypoglycemia awareness (Gold instrument), hypoglycemia beliefs (Attitudes to Awareness of Hypoglycemia instrument), CGM glycemic profiles, demographics, and anxiety and depression symptoms (Hospital Anxiety and Depression Scale). Analysis included simple and multiple linear regression analyses. RESULTS: Lower hypoglycemia awareness, weaker "hypoglycemia concerns minimized" beliefs, stronger "hyperglycemia avoidance prioritized" beliefs were independently associated with higher anxiety symptoms (P < 0.05), with similar trends in both subgroups using and not using AIDs. Lower hypoglycemia awareness were independently associated with greater depression symptoms (P < 0.05). In participants not using AIDs, more time in hypoglycemia was related to less anxiety and depression symptoms (P < 0.05). Being female and younger were independently associated with higher anxiety symptoms, while being younger was also independently associated with greater depression symptoms (P < 0.05). CONCLUSION: Our findings revealed relationships of impaired hypoglycemia awareness, hypoglycemia beliefs, CGM-detected hypoglycemia with anxiety and depression symptoms in T1D adults who use CGMs.

Effective management of recurrent Doege-Potter syndrome with somatostatin-analogues: A case report.

BACKGROUND: Doege-Potter syndrome is defined as paraneoplastic hypoinsulinemic hypoglycemia associated with a benign or malignant solitary fibrous tumor frequently located in pleural, but also extrapleural sites. Hypoglycemia can be attributed to paraneoplastic secretion of "Big-IGF-II," a precursor of Insulin-like growth factor-II. This prohormone aberrantly binds to and activates insulin receptors, with consecutive initiation of common insulin actions such as inhibition of gluconeogenesis, activation of glycolysis and stimulation of cellular glucose uptake culminating in recurrent tumor-induced hypoglycemic episodes. Complete tumor resection or debulking surgery is considered the most promising treatment for DPS. CASE: Here, we report a rare case of a recurrent Doege-Poter Syndrome with atypical gelatinous tumor lesions of the lung, pleura and pericardial fat tissue in an 87-year-old woman. Although previously described as ineffective, we propose that adjuvant treatment with Octreotide in conjunction with intravenous glucose helped to maintain tolerable blood glucose levels before tumor resection. The somatostatin-analogue Lanreotide was successfully used after tumor debulking surgery (R2-resection) to maintain adequate blood glucose control. CONCLUSION: We conclude that somatostatin-analogues bear the potential of being effective in conjunction with limited surgical approaches for the treatment of hypoglycemia in recurrent or non-totally resectable SFT entities underlying DPS.

Postbariatric hypoglycemia, abdominal pain and gastrointestinal symptoms after Roux-en-Y gastric bypass explored by continuous glucose monitoring.

BACKGROUND: Abdominal pain and postbariatric hypoglycemia (PBH) are common after bariatric surgery. OBJECTIVES: This study aimed to explore the potential relationship between abdominal pain, gastrointestinal symptoms, and PBH more than a decade after Roux-en-Y gastric bypass (RYGB) and whether continuous glucose monitoring (CGM) with dietary intervention has an educational role in reducing symptoms. SUBJECTS: At two public hospitals in Norway (one University Hospital) 22 of 46 invited patients who reported abdominal pain more than weekly took part. Recruited from a prospective follow-up study of 546 patients 14.5 years after RYGB. METHODS: They used a CGM for two 14-day periods, with a dietary intervention between periods. The Gastrointestinal Symptom Rating Scale (GSRS) and the Dumping Severity Score (DSS) questionnaires were completed at the start and end of the study. RESULTS: The 22 women had preoperative age 39.6 ± 7.7 years and body mass index (BMI) 42.0 ± 4.0 kg/m2, present age 54.6 ± 7.7 years and BMI 29.8 ± 4.8 kg/m2. The total GSRS score and DSS of early dumping decreased after the diet intervention. The number of events with Level 1 (<3.9 mmol/L) or Level 2 (<3.0 mmol/L) hypoglycemia did not change in the second period. Half of the patients had fewer, three had unchanged, and eight had more frequent events with Level 1 hypoglycemia after the intervention. Ten patients had Level 2 hypoglycemia. CONCLUSION: Though inconclusive findings, a personalized dietary intervention reduces GSRS. This intervention was accompanied by lower mean absolute glucose in patients with recurrent abdominal pain after bariatric surgery. However, further studies are needed to explore the benefits of CGM in this setting.

Vagal activation alters prandial bile acid composition and glycemia in patients with hypoglycemia after Roux-en-Y gastric bypass surgery.

BACKGROUND: Altered prandial glycemic response after Roux-en-Y gastric bypass (RYGB) is exaggerated in patients with post-RYGB hypoglycemia. Increased contribution of glucagon-like peptide 1 (GLP-1) to prandial insulin secretion plays a key role in developing hypoglycemia after RYGB, but the role of nonhormonal gut factors remains unknown. Here, the effect of vagal activation on prandial bile acid (BA) composition in relation to glucose, insulin and gut hormone responses was examined in a small size group of nondiabetic subjects after RYGB with intact gallbladder compared to nonoperated controls. METHODS: Concentrations of blood glucose, hormones, and BAs were measured in two RYGB subjects with documented hypoglycemia (HGB), three asymptomatic RYGB-treated subjects (AGB), and four nonoperated controls with intact gallbladders during a meal-tolerance test with (MTT-Sham) and without (MTT) preceding modified sham feeding (chew and spit). KEY RESULTS: Meal ingestion raised serum total BAs in RYGB-treated subjects without any effect in nonoperated controls. Modified sham feeding similarly increased meal-induced responses of conjugated BAs (CBAs) in all subjects (p < 0.05 compared to MTT alone), whereas unconjugated BAs (UBAs), mainly deoxycholic and chenodeoxycholic acid, were raised only in the HGB group (p < 0.001 for interaction). Prandial UBAs had an inverse correlation with glucose nadir (r = -0.75, p < 0.05) and were directly associated with ISR and GLP-1 during MTT-Sham. CONCLUSIONS & INFERENCES: In this small cohort, vagal activation by modified sham feeding increases prandial CBAs in both operated and nonoperated subjects but enhances UBAs only in patients with documented post-RYGB hypoglycemia. Our findings highlight a potential role for nonhormonal gut factors, such as BA and gut microbiome, in glucose abnormalities after RYGB.

Malglycemia in the critical care setting. Part III: Temporal patterns, relative potencies, and hospital mortality.

INTRODUCTION: The relationship between critical care mortality and combined impact of malglycemia remains undefined. METHODS: We assessed the risk-adjusted relationship (n = 4790) between hospital mortality with malglycemia, defined as hypergycemia (hours Glycemic Ratio ≥ 1.1, where GR is quotient of mean ICU blood glucose (BG) and estimated average BG), absolute hypoglycemia (hours BG < 70 mg/dL) and relative hypoglycemia (excursions GR < 0.7 in those with HbA1c ≥ 8%). RESULTS: Each malglycemia was independently associated with mortality - hyperglycemia (OR 1.0020/h, 95%CI 1.0009-1.0031, p = 0.0004), absolute hypoglycemia (OR 1.0616/h, 95%CI 1.0190-1.1061, p = 0.0043), and relative hypoglycemia (OR 1.2813/excursion, 95%CI 1.0704-1.5338, p = 0.0069). Absolute (7.4%) and relative hypoglycemia (6.7%) exposure dominated the first 24 h, decreasing thereafter. While hyperglycemia had lower risk association with mortality, it was persistently present across the length-of-stay (68-76% incidence daily), making it the dominant form of malglycemia. Relative contributions in the first five days from hyperglycemia, absolute hypoglycemia and relative hypoglycemia were 60%, 21% and 19% respectively. CONCLUSIONS: Absolute and relative hypoglycemia occurred largely in the first 24 h. Relative to all hypoglycemia, the associated mortality from the seemingly less potent but consistently more prevalent hyperglycemia steadily accumulated with increasing length-of-stay. This has important implications for interpretation of study results.

A systematic review of literature on Insulin-like growth factor-2-mediated hypoglycaemia in non-islet cell tumours.

INTRODUCTION: Insulin-like growth factor-2 (IGF-2)-mediated hypoglycemia is a rare yet clinically significant entity with considerable morbidity and mortality. Existing literature is limited and fails to offer a comprehensive understanding of its clinical trajectory, management and prognostication. METHODS: Systematic review of English-language articles reporting primary patient data on IMH was searched using electronic databases (PubMed, Scopus and Embase) from any date up to 21 December 2022. Data were analysed in STATA-16. RESULTS: The systematic review contains 172 studies, including 1 Randomised controlled trial, 1 prospective observational study, 5 retrospective observational studies, 150 case reports, 11 case series and 4 conference abstracts. A total of 233 patients were analysed, averaging 60.6 ± 17.1 years in age, with comparable proportions of males and females. The commonest tumours associated with Insulin-like Growth Factor-2-mediated hypoglycaemia were fibrous tumours (N = 124, 53.2%), followed by non-fibrous tumours originating from the liver (N = 21, 9%), hemangiopericytomas (N = 20, 8.5%) and mesotheliomas (N = 11, 4.7%). Hypoglycaemia was the presenting feature of NICT in 42% of cases. Predominant clinical features included loss of consciousness (26.7%) and confusion (21%). The mean IGF-2 and IGF-1 levels were 882.3 ± 630.6 ng/dL and 41.8 ± 47.8, respectively, with no significant correlation between these levels and patient outcomes. Surgical removal was the most employed treatment modality (47.2%), followed by medication therapy. The recovery rate was 77%, with chronic liver disease (CLD) significantly associated with a poor outcome (OR: 7.23, P: 0.03). Tumours originating from fibrous tissues were significantly associated with recovery (p < .001). In the logistic regression model, CLD remained a significant predictor of poor outcomes. CONCLUSION: This systematic review highlights that most non-islet-cell tumour-hypoglycaemia (NICTH) is due to fibrous tumours. NICTs demonstrate a variable prognosis, which is fair if originating from fibrous tissue. Management such as octreotide, corticosteroids, diazoxide, embolization, radiotherapy and surgical resection have disparate success rates.

Use of machine learning to identify characteristics associated with severe hypoglycemia in older adults with type 1 diabetes: a post-hoc analysis of a case-control study.

INTRODUCTION: Severe hypoglycemia (SH) in older adults (OAs) with type 1 diabetes is associated with profound morbidity and mortality, yet its etiology can be complex and multifactorial. Enhanced tools to identify OAs who are at high risk for SH are needed. This study used machine learning to identify characteristics that distinguish those with and without recent SH, selecting from a range of demographic and clinical, behavioral and lifestyle, and neurocognitive characteristics, along with continuous glucose monitoring (CGM) measures. RESEARCH DESIGN AND METHODS: Data from a case-control study involving OAs recruited from the T1D Exchange Clinical Network were analyzed. The random forest machine learning algorithm was used to elucidate the characteristics associated with case versus control status and their relative importance. Models with successively rich characteristic sets were examined to systematically incorporate each domain of possible risk characteristics. RESULTS: Data from 191 OAs with type 1 diabetes (47.1% female, 92.1% non-Hispanic white) were analyzed. Across models, hypoglycemia unawareness was the top characteristic associated with SH history. For the model with the richest input data, the most important characteristics, in descending order, were hypoglycemia unawareness, hypoglycemia fear, coefficient of variation from CGM, % time blood glucose below 70 mg/dL, and trail making test B score. CONCLUSIONS: Machine learning may augment risk stratification for OAs by identifying key characteristics associated with SH. Prospective studies are needed to identify the predictive performance of these risk characteristics.

Fear of hypoglycemia and illness perception in type II diabetes patients.

BACKGROUND: Hypoglycemia, a prevalent acute complication among individuals with type 2 diabetes (T2D), manifests with varied symptoms. Those with diabetes who have previously encountered hypoglycemic episodes commonly develop a Fear of Hyperglycemia (FOH). Illness perception (IP) significantly affects self-care behaviors and health outcomes in individuals diagnosed with T2D. OBJECTIVE: This study examined the correlation between IP and FOH among T2D patients and predictors of FOH. METHODS: The present study employed a descriptive-analytical design. The target population for this investigation comprised patients diagnosed T2D who sought medical care at the clinic and endocrinology departments of a hospital affiliated with Alborz University of Medical Sciences. The data collection period spanned from August 2019 to March 2021. A total of 300 individuals were included in the sample. Questionnaires were administered to measure both IP and FOH. Statistical analysis was conducted to examine the association between IP and FOH, as well as to identify the predictors of FOH. RESULTS: The results of the study indicated a statistically significant relationship between FOH and the mean score of IP among patients with diabetes (p = 0.001, r = 0.393), suggesting a moderate positive correlation between these variables. Additionally, the duration of illness, IP, and level of education were identified as variables that predicted FOH (p < 0.05). CONCLUSION: The numerous factors that influence FOH in individuals diagnosed with T2D highlight the necessity for strategic planning and training initiatives aimed at enhancing IP and reducing FOH within this specific population. Healthcare providers should prioritize interventions that not only address patients' concerns but also contribute to the improvement of their overall well-being. By implementing such interventions, healthcare providers can optimize diabetes management strategies and ultimately enhance patient outcomes.

Decreasing the Burden of Carbohydrate Counting and Meal Announcement with Automated Insulin Delivery, Meal Recognition, and Autocorrection Doses: A Case Study.

The use of automated insulin delivery (AID) has led to a decrease in the burden of diabetes, allowing for better sleep, decreased anxiety about hypoglycemia, and automatic corrections doses, and meal recognition algorithms have provided "forgiveness" for imprecise carbohydrate (CHO) entries and missed or late meal boluses. We provide a case report and review of the current literature assessing the effect of AID on the burden of meal bolus. The case also demonstrates how sensor and pump data provide insight into insulin bolus behavior, and access to integrated cloud-based data has allowed for virtual patient visits. Glucose sensor metrics provides time in range and time below range, and the sensor-derived glucose management indicator provides an assessment of the long-term risk of complications when a laboratory glycated hemoglobin is not available.

Intraoperative segmental pancreatic occlusion and insulin assay combination optimizes the localization of lesions and confirmation of complete resection in pancreatic hypoglycemia patients.

AIM: To evaluate the efficacy of the application of intraoperative segmental pancreatic occlusion and insulin assay in surgical procedures for pancreatic hypoglycemia. METHODS: We retrospectively analyzed the clinical data of 11 pancreatic hypoglycemia cases treated in the China-Japan Friendship Hospital between September 2015 and August 2021. Intraoperative segmental pancreatic occlusion and insulin assay were used to enhance hypersecretory pancreatic tissues' localization and to achieve a complete resection. Intraoperative testing of insulin levels (peripheral venous blood) was carried out at several time points starting from before the resection of hypersecretory tissues (base value) and at 1 minute, 5 minutes, 15 minutes, 30 minutes, and 60 minutes after resection. Additional testing every 30 minutes until the end of the operation was carried out when necessary. RESULTS: A total of 11 pancreatic hypoglycemia cases were included; 9 cases were insulinomas (all with single pancreatic lesions, with 4 located in the head, 1 in the body, and 4 in the tail), 1 MEN-1, and 1 nesidioblastosis. The insulin assay (30 minutes after the resection of hypersecretory tissues) enhanced the ability to locate target tissues and the accuracy of complete resection to 100%. As for intraoperative blood glucose monitoring, the accuracy 30 minutes after resection was as low as 36.6%. Postoperative levels of insulin and glucose were normal in all patients, with no recurrence of hypoglycemic symptoms during postoperative follow-up visits (9 to 72 months). CONCLUSION: Intraoperative segmental pancreatic occlusion and insulin assay in pancreatic hypoglycemia is a simple, accurate, and fast approach that enhances the localization and complete resection of hypersecretory tissues. Such a combination is highly significant in challenging cases of hypoglycemia.

Development and validation of a prediction model for self-reported hypoglycemia risk in patients with type 2 diabetes: A longitudinal cohort study.

AIMS/INTRODUCTION: To develop and validate a simple prediction model for hypoglycemia risk in patients with type 2 diabetes. MATERIALS AND METHODS: We prospectively analyzed the data of 1,303 subjects in a third-class hospital in Tianjin and followed up their hypoglycemia events at 3 and 6 months. The hypoglycemia risk prediction models for 3 and 6 months were developed and the model performance was evaluated. RESULTS: A total of 340 (28.4%) patients experienced hypoglycemia within 3 months and 462 (37.2%) within 6 months during the follow-up period. Age, central obesity, intensive insulin therapy, frequency of hypoglycemia in the past year, and hypoglycemia prevention education entered both model3month and model6month. The area under the receiver operating characteristic curve of model3month and model6month were 0.711 and 0.723, respectively. The Youden index was 0.315 and 0.361, while the sensitivities were 0.615 and 0.714, and the specificities were 0.717 and 0.631. The calibration curves showed that the models were similar to reality. The decision curves implied that the clinical net benefit of the model was clear. CONCLUSIONS: The study developed 3 and 6 month hypoglycemia risk prediction models for patients with type 2 diabetes. The discrimination and calibration of the two prediction models were good, and might help to improve clinical decision-making and guide patients to more reasonable self-care and hypoglycemia prevention at home.

Neonatal hypoglycemia and neurodevelopmental outcomes: Yesterday, today, tomorrow.

Neonatal hypoglycemia is a major source of concern for pediatricians since it has commonly been related to poor neurodevelopmental outcomes. Diagnosis is challenging, considering the different operational thresholds provided by each guideline. Screening of infants at risk plays a crucial role, considering that most hypoglycemic infants show no clinical signs. New opportunities for prevention and treatment are provided by the use of oral dextrose gel. Continuous glucose monitoring systems could be a feasible tool in the next future. Furthermore, there is still limited evidence to underpin the current clinical practice of administering, in case of hypoglycemia, an intravenous "mini-bolus" of 10% dextrose before starting a continuous dextrose infusion. This brief review provides an overview of the latest advances in this field and neurodevelopmental outcomes according to different approaches.   Conclusion: To adequately define if a more permissive approach is risk-free for neurodevelopmental outcomes, more research on continuous glucose monitoring and long-term follow-up is still needed. What is Known: • Neonatal hypoglycemia (NH) is a well-known cause of brain injury that could be prevented to avoid neurodevelopmental impairment. • Diagnosis is challenging, considering the different suggested operational thresholds for NH (<36, <40, <45, <47 or <50 mg/dl). What is New: • A 36 mg/dl threshold seems to be not associated with a worse psychomotor development at 18 months of life when compared to the "traditional" threshold (47 mg/dl). • Further studies on long-term neurodevelopmental outcomes are required before suggesting a more permissive management of NH.