Robotic Resection in Succinate Dehydrogenase Subunit B (SDHB)-Mutated Hereditary Paraganglioma: A Case Report of Two Patients and A Literature Review.

Autosomal dominant hereditary paraganglioma-pheochromocytoma syndrome (HPPS) is a rare genetic disorder characterized by neuroendocrine tumor development associated with pathogenic variants in succinate dehydrogenase (SDH) enzyme complex genes. Particularly, HPPS linked to SDHB mutation poses a significant clinical challenge due to its association with aggressive tumor features and a high risk of malignancy. Our report underscores the diversity in the presentation of patients with SDHB-mutated paraganglioma and the feasibility of managing it with a minimally invasive surgical approach. In the first case, a 17-year-old female was diagnosed with a metabolically active, poorly differentiated extra-adrenal retroperitoneal paraganglioma that required challenging robotic resection. Cascade genetic testing revealed an SDHB mutation not only in her but also in three family members, pointing to the inherited nature of the syndrome. Conversely, the second case involves a 37-year-old male with an asymptomatic well-differentiated left paraaortic paraganglioma incidentally found during an unrelated medical examination. Robotic converted-to-open resection allowed the successful removal of the mass. Subsequent germline testing confirmed a deleterious SDHB mutation, initiating a process of familial cascade testing. Both patients remained symptom- and recurrence-free at 12 and six months, respectively. Through these cases, and supported by a literature review, we highlight the variable clinical presentations of HPPS, arising from the same genetic alteration. The successful application of minimally invasive surgical techniques, combined with genetic evaluation, emphasizes the necessity for a comprehensive, tailored approach to treatment and surveillance. This strategy not only addresses the immediate clinical needs but also fosters proactive management of at-risk family members, ensuring a multidisciplinary approach to this complex hereditary condition.

Time to Move Beyond a Binary Criterion for Gestational Diabetes?

Over the years, several international guidelines have been developed by specialist organizations for the diagnosis of gestational diabetes mellitus (GDM). However, these guidelines vary and lack consensus on what level of glycemia defines GDM and worryingly, there is now evidence of over- or- under-diagnosis of women with GDM by current criteria. Towards this end, the National Priorities Research Program (NPRP) funded a program of research aimed at elucidating the problem with GDM diagnosis. It was determined, on completion of the project, that the solution required diagnosis of graded levels of dysglycemia in pregnancy and not just a diagnosis of presence or absence of GDM. A new diagnostic criterion (called the NPRP criterion) was created based on a single numerical summary of the three readings from the oral glucose tolerance test (GTT) that diagnosed women in pregnancy into four levels: normal, impaired, GDM and high risk GDM. This paper now examines existing GDM criteria vis-à-vis the NPRP criterion. It is noted that no significant change has happened over the years for existing criteria except for a gradual reduction in the threshold values of individual time-points or the number of time points, bringing us towards over-diagnosis of GDM in pregnancy. The new criterion unifies all readings from the GTT into one numerical value and, because it results in four levels of glycemia, represents a new way forwards for GDM diagnosis and can potentially reduce the rates of under diagnosis and over diagnosis of GDM.

Evaluating the adoption of voice recognition technology for real-time dictation in a rural healthcare system: A retrospective analysis of dragon medical one.

BACKGROUND: In 2013, Marshfield Clinic Health System (MCHS) implemented the Dragon Medical One (DMO) system provided by Nuance Management Center (NMC) for Real-Time Dictation (RTD), embracing the idea of streamlined clinic workflow, reduced dictation hours, and improved documentation legibility. Since then, MCHS has observed a trend of reduced time in documentation, however, the target goal of 100% adoption of voice recognition (VR)-based RTD has not been met. OBJECTIVE: To evaluate the uptake/adoption of VR technology for RTD in MCHS, between 2018-2020. METHODS: DMO data for 1,373 MCHS providers from 2018-2020 were analyzed. The study outcome was VR uptake, defined as the median number of hours each provider used VR technology to dictate patient information, and classified as no/yes. Covariates included sex, age, US-trained/international medical graduates, trend, specialty, and facility. Descriptive statistics and unadjusted and adjusted logistic regression analyses were performed. Stata/SE.version.17 was used for analyses. P-values less than/equal to 0.05 were considered statistically significant. RESULTS: Of the 1,373 MCHS providers, the mean (SD) age was 48.3 (12.4) years. VR uptake was higher than no uptake (72.0% vs. 28.0%). In both unadjusted and adjusted analyses, VR uptake was 4.3 times and 7.7 times higher in 2019-2020 compared to 2018, respectively (OR:4.30,95%CI:2.44-7.46 and AOR:7.74,95%CI:2.51-23.86). VR uptake was 0.5 and 0.6 times lower among US-trained physicians compared to internationally-trained physicians (OR:0.53,95%CI:0.37-0.76 and AOR:0.58,95%CI:0.35-0.97). Uptake was 0.2 times lower among physicians aged 60/above than physicians aged 29/less (OR:0.20,95%CI:0.10-0.59, and AOR:0.17,95%CI:0.27-1.06). CONCLUSION: Since 2018, VR adoption has increased significantly across MCHS. However, it was lower among US-trained physicians than among internationally-trained physicians (although internationally physicians were in minority) and lower among more senior physicians than among younger physicians. These findings provide critical information about VR trends, physician factors, and which providers could benefit from additional training to increase VR adoption in healthcare systems.

Unifying the diagnosis of gestational diabetes mellitus: Introducing the NPRP criteria.

AIMS: Disagreement about the appropriate criteria for the diagnosis of gestational diabetes mellitus (GDM) persists. This study examines an alternative approach which combines information from all time-points on the glucose tolerance test (GTT) into a single index and expands the GDM spectrum into four categories using data from three geographically and ethnically distinct populations. METHODS: A retrospective observational study design was used. Data from Wisconsin, USA (723 women) was used in derivation of the criterion and data from Doha, Qatar (1284 women) and Cape Town, South Africa (220 women) for confirmation. Pregnant women without pre-existing diabetes with a GTT done between 23 and 30 weeks gestation were included. A novel index was derived from the GTT termed the weighted average glucose (wAG). This was categorized into four pre-defined groups (henceforth National Priorities Research Program (NPRP) criterion); i) normal gestational glycemia (NGG), ii) impaired gestational glycemia (IGG), iii) GDM and iv) high risk GDM (hGDM). RESULTS: In the Doha cohort, compared to the NGG group, the odds of large for gestational age babies increased 1.33 fold (P = 0.432), 2.86 fold (P < 0.001) and 3.35 fold (P < 0.001) in the IGG, GDM and hGDM groups respectively. The odds of pregnancy induced hypertension increased 2.10 fold (P = 0.024) in GDM & hGDM groups compared to the IGG and NGG groups. In the Cape Town cohort, a third of women in the GDM group and two-thirds in the hGDM group progressed to T2DM at 5 years. CONCLUSIONS: The NPRP categorization identifies four distinct risk clusters of glycemia in pregnancy which may aid better decision making in routine management, avoid potential over-diagnosis of women at lower risk of complications and assist with diabetes prevention in women at high-risk after an index pregnancy with GDM.

Frequency of Parathyroid Hormone Assessment in the Evaluation of Hypercalcemia. A Comparison Between Patients With and Without a History of Malignancy in a 20-year Dataset of 20,954 Patients.

BACKGROUND: The purpose of this study was to evaluate whether a prior diagnosis of malignancy affected the assessment of parathyroid hormone (PTH) in hypercalcemic patients and whether the rate of this assessment changed over time. METHODS: A retrospective cohort study was designed that included adult patients with hypercalcemia with and without a history of malignancy between January 1, 2000 and December 31, 2019 in the Marshfield Clinic Health System (MCHS). The overall and annual rates of PTH assessment in each group was determined. In patients with a PTH assessment, duration of time and number of elevated serum calcium levels between the first documentation of hypercalcemia and the assessment of PTH were recorded, as was the degree of hypercalcemia. RESULTS: Approximately a quarter (23%) of the patients in each group had a PTH assessment. The rate of PTH assessment initially increased over time but later declined significantly. Although a more severe degree of hypercalcemia predicted a greater probability of PTH assessment, the rate of assessment declined with all degrees of hypercalcemia in the last 5 years. While most patients who had a PTH assessed did so within a few months of the first documentation of hypercalcemia, less than half (40%) had a delay of more than 2 years before a PTH level was drawn. CONCLUSION: This lack of appropriate and timely assessment may have significant health consequences in both groups of patients. Better education of providers about the appropriate and timely assessment of PTH in the evaluation of hypercalcemia is urgently needed.

Evaluation of Diagnostic Workup and Etiology of Hypercalcemia of Malignancy in a Cohort of 167 551 Patients Over 20 Years.

CONTEXT: Hypercalcemia of malignancy (HCM) has not been studied in a fashion to determine all possible mechanisms of hypercalcemia in any given patient. OBJECTIVE: The 2 objectives were to assess the completeness of evaluation and to determine the distribution of etiologies of HCM in a contemporary cohort of patients. METHODS: A retrospective analysis was performed of patients with cancer who developed hypercalcemia over 20 years at a single health system. Laboratory data were electronically captured from medical records to identify cases of parathyroid hormone (PTH)-independent hypercalcemia. The records were then manually reviewed to confirm the diagnosis of HCM, document the extent of evaluation, and determine underlying etiology(ies) of HCM in each patient. RESULTS: The initial data set included 167 551 adult patients with malignancy, of which 11 589 developed hypercalcemia. Of these, only a quarter (25.4%) had assessment of PTH with a third of the latter (30.9%) indicating PTH-independent hypercalcemia. Of those with PTH-independent hypercalcemia, a third (31.6%) had assessment of PTH-related peptide (PTHrP) and/or 1,25-dihydroxy (1,25-OH) vitamin D and constituted the 153 cases of HCM examined in this study. Eighty-three of these patients had an incomplete evaluation of their HCM. The distribution of etiologies of HCM was therefore determined from the remaining 70 patients who had assessment of all 3 possible etiologies (PTHrP, 1,25-OH vitamin D, and skeletal imaging) and was as follows: PTHrP, 27%; osteolytic metastases, 50%; and 1,25-OH vitamin D, 39%, with combinations of etiologies being common (approximately 20%). CONCLUSION: HCM is incompletely evaluated in many patients. The distribution of etiologies of HCM in this report differs significantly from the previous literature, warranting further study to determine whether its causes have indeed changed over time.

Oral cinacalcet responsiveness in non-parathyroid hormone mediated hypercalcemia of malignancy.

Hypercalcemia of malignancy develops in approximately 20-30% of patients with advanced cancer and is an ominous sign. This condition is subdivided into three categories: i) humoral hypercalcemia of malignancy (80% of cases), mediated by systemic parathyroid hormone-related protein; ii) osteolytic metastases (20% of cases), mediated by inflammatory cytokines locally released by tumor cells and/or peri-tumor macrophages; and iii) ectopic production of 1,25-dihydroxyvitamin D (<1% of cases), leading to intestinal hyperabsorption of calcium and increased osteoclastic bone resorption. Humoral hypercalcemia of malignancy is seen in a variety of solid tumors, while osteolytic metastases are most common in breast cancer and multiple myeloma. Hypercalcemia of malignancy mediated by 1,25-dihydroxyvitamin D is primarily seen in lymphomas, having only rarely been reported in solid tumors. Pharmacologic management of humoral hypercalcemia of malignancy and osteolytic metastases mainly involves inhibition of bone resorption with intravenous bisphosphonates, subcutaneous denosumab, and subcutaneous calcitonin. Glucocorticoid therapy is the mainstay for management of increased 1,25-dihydroxyvitamin D. Unfortunately, management of hypercalcemia of malignancy often requires inpatient admission in the acute setting, and loss of effectiveness of antiresorptive therapy is common. We propose oral cinacalcet may be an efficacious therapy for hypercalcemia of malignancy related to elevated 1,25-dihydroxyvitamin D, and we present supporting data from two cases involving solid tumors. Furthermore, we hypothesize that this effect is primarily mediated by cinacalcet's interaction with the calcium-sensing receptor in the intestine with lesser effects at bone and kidney. Lastly, the role of 1,25-dihydroxyvitamin D in hypercalcemia malignancy may be underappreciated in solid tumors.

Biochemical Testing of the Thyroid: TSH is the Best and, Oftentimes, Only Test Needed - A Review for Primary Care.

Disorders of thyroid function are common, and screening, diagnosis, and management are often performed by primary care providers. While management of significant biochemical abnormalities is reasonably straight forward, laboratory tests only slightly outside, or even within, the normal range are becoming more difficult to appropriately manage. A large part of this increasing difficulty in appropriate management is caused by patients requesting, and even demanding, certain tests or treatments that may not be indicated. Symptoms of thyroid dysfunction are non-specific and extremely prevalent in the general population. This, along with a growing body of information available to patients via the lay press and internet suggesting that traditional thyroid function testing is not reliable, has fostered some degree of patient mistrust. Increasingly, when a physician informs a patient that their thyroid is not the cause of their symptoms, the patient is dissatisfied and even angry. This review aims to clarify the interpretation of normal and mild abnormalities of thyroid function tests by describing pituitary-thyroid physiology and through an in depth review of, arguably, the three most important biochemical tests of thyroid function: TSH, free T4, and anti-TPO antibodies. It is important for primary care providers to have an understanding of the shortcomings and proper interpretation of these tests to be better able to discuss thyroid function with their patients.

Transient Hypothyroidism after Radioiodine for Graves' Disease: Challenges in Interpreting Thyroid Function Tests.

Graves' disease is the most common cause of hyperthyroidism and is often managed with radioactive iodine (RAI) therapy. With current dosing schemes, the vast majority of patients develop permanent post-RAI hypothyroidism and are placed on life-long levothyroxine therapy. This hypothyroidism typically occurs within the first 3 to 6 months after RAI therapy is administered. Indeed, patients are typically told to expect life-long thyroid hormone replacement therapy to be required within this timeframe and many providers expect this post-RAI hypothyroidism to be complete and permanent. There is, however, a small subset of patients in whom a transient post-RAI hypothyroidism develops which, initially, presents exactly as the typical permanent hypothyroidism. In some cases the transient hypothyroidism leads to a period of euthyroidism of variable duration eventually progressing to permanent hypothyroidism. In others, persistent hyperthyroidism requires a second dose of RAI. Failure to appreciate and recognize the possibility of transient post-RAI hypothyroidism can delay optimal and appropriate treatment of the patient. We herein describe five cases of transient post-RAI hypothyroidism which highlight this unusual sequence of events. Increased awareness of this possible outcome after RAI for Graves' disease will help in the timely management of patients.

Hyperinsulinemia and skeletal muscle fatty acid trafficking.

We hypothesized that insulin alters plasma free fatty acid (FFA) trafficking into intramyocellular (im) long-chain acylcarnitines (imLCAC) and triglycerides (imTG). Overnight-fasted adults (n = 41) received intravenous infusions of [U-¹³C]palmitate (0400-0900 h) and [U-¹³C]oleate (0800-1400 h) to label imTG and imLCAC. A euglycemic-hyperinsulinemic (1.0 mU·kg fat-free mass⁻¹·min⁻¹) clamp (0800-1400 h) and two muscle biopsies (0900 h, 1400 h) were performed. The patterns of [U-¹³C]palmitate incorporation into imTG-palmitate and palmitoylcarnitine were similar to those we reported in overnight postabsorptive adults (saline control); the intramyocellular palmitoylcarnitine enrichment was not different from and correlated with imTG-palmitate enrichment for both the morning (r = 0.38, P = 0.02) and afternoon (r = 0.44, P = 0.006) biopsy samples. Plasma FFA concentrations, flux, and the incorporation of plasma oleate into imTG-oleate during hyperinsulinemia were ~1/10th of that observed in the previous saline control studies (P < 0.001). At the time of the second biopsy, the enrichment in oleoylcarnitine was <25% of that in imTG-oleate and was not correlated with imTG-oleate enrichment. The intramyocellular nonesterified fatty acid-palmitate-to-imTG-palmitate enrichment ratio was greater (P < 0.05) in women than men, suggesting that sex differences in intramyocellular palmitate trafficking may occur under hyperinsulinemic conditions. We conclude that plasma FFA trafficking into imTG during hyperinsulinemia is markedly suppressed, and these newly incorporated FFA fatty acids do not readily enter the LCAC preoxidative pools. Hyperinsulinemia does not seem to inhibit the entry of fatty acids from imTG pools that were labeled under fasting conditions, possibly reflecting the presence of two distinct imTG pools that are differentially regulated by insulin.

Relationship between plasma free fatty acid, intramyocellular triglycerides and long-chain acylcarnitines in resting humans.

We hypothesized that plasma non-esterified fatty acids (NEFA) are trafficked directly to intramyocellular long-chain acylcarnitines (imLCAC) rather than transiting intramyocellular triglycerides (imTG) on the way to resting muscle fatty acid oxidation. Overnight fasted adults (n = 61) received intravenous infusions of [U-(13)C]palmitate (0400-0830 h) and [U-(13)C]oleate (0800-1400 h) labelling plasma NEFA, imTG, imLCAC and im-non-esterified FA (imNEFA). Two muscle biopsies (0830 and 1400 h) were performed following 6 h, overlapping, sequential palmitate/oleate tracer infusions. Enrichment of plasma palmitate was approximately 15 times greater than enrichment of imTG, imNEFA-palmitate and im-palmitoyl-carnitine. Fatty acid enrichment in LCAC was correlated with imTG and imNEFA; there was a significant correlation between imTG concentrations and imLCAC concentrations in women (r = 0.51, P = 0.005), but not men (r = 0.30, P = 0.11). We estimated that approximately 11% of NEFA were stored in imTG. imTG NEFA storage was correlated only with NEFA concentrations (r = 0.52, P = 0.004) in women and with V(O(2),peak) (r = 0.45, P = 0.02) in men. At rest, plasma NEFA are trafficked largely to imTG before they enter LCAC oxidative pools; thus, imTG are an important, central pool that regulates the delivery of fatty acids to the intracellular environment. Factors relating to plasma NEFA storage into imTG differ in men and women.

Silent thyroiditis, isolated corticotropin deficiency, and alopecia universalis in a patient with ulcerative colitis and elevated levels of plasma factor VIII: an unusual case of autoimmune polyglandular syndrome type 3.

OBJECTIVE: To describe an unusual case of autoimmune polyglandular syndrome (APS) type 3 and provide a brief review of the literature. METHODS: We present the clinical course and laboratory data of a patient with silent thyroiditis, isolated corticotropin (adrenocorticotropic hormone or ACTH) deficiency, alopecia universalis, and ulcerative colitis with an associated hypercoagulable state. The related literature is also reviewed briefly. RESULTS: A 43-year-old man who had a history of ulcerative colitis with an associated hypercoagulable state and alopecia universalis was referred to the endocrinology department for evaluation of fatigue and a mildly elevated level of thyrotropin (thyroid-stimulating hormone or TSH). He previously had mildly increased TSH levels, for which low-dose levothyroxine therapy had been prescribed. During use of this therapy, a suppressed TSH level developed, necessitating discontinuation of thyroid hormone therapy; a subsequent increase in TSH value was followed by a spontaneous return to euthyroidism. An ACTH stimulation test revealed adrenal insufficiency. His ACTH level was low, 21-hydroxylase antibodies were not present, and further testing demonstrated otherwise intact pituitary function. Magnetic resonance imaging of his pituitary gland showed normal findings. Treatment with hydrocortisone promptly decreased his fatigue. He was found to have an elevated factor VIII level as the cause of his hypercoagulable state. The patient continues to feel well with use of hydrocortisone therapy and has normal thyroid function. CONCLUSION: This patient's components of APS type 3 have not been previously reported; thus, the complex nature of the APS variants is supported.

Basal and insulin-regulated free fatty acid and glucose metabolism in humans.

These studies were done to examine the effects of body composition, resting energy expenditure (REE), sex, and fitness on basal and insulin-regulated FFA and glucose metabolism. We performed 137 experiments in 101 nondiabetic, premenopausal women and men, ranging from low normal weight to class III obese (BMI 18.0-40.5 kg/m2). Glucose flux was measured using [6-(2)H2]glucose and FFA kinetics with [9,10-(3)H]oleate under either basal (74 experiments) or euglycemic hyperinsulinemic (1.0 mU.kg FFM(-1).min(-1)) clamp conditions (63 experiments). Consistent with our previous findings, REE and sex independently predicted basal FFA flux, whereas fat-free mass was the best predictor of basal glucose flux; in addition, percent body fat was independently and positively associated with basal glucose flux (total r2 = 0.52, P < 0.0001). Insulin-suppressed lipolysis remained significantly associated with REE (r = 0.25, P < 0.05), but percent body fat also contributed (total adjusted r2 = 0.36, P < 0.0001), whereas sex was not significantly related to insulin-suppressed FFA flux. Glucose disposal during hyperinsulinemia was independently associated with peak VO2, percent body fat, and FFA concentrations (total r2 = 0.63, P < 0.0001) but not with sex. We conclude that basal glucose production is independently related to both FFM and body fatness. In addition, hyperinsulinemia obscures the sex differences in FFA release relative to REE, but brings out the effects of fatness on lipolysis.

Polycystic ovarian syndrome: diagnosis and management.

Polycystic ovarian syndrome (PCOS) affects 4% to 12% of women of reproductive age. The lack of well-defined diagnostic criteria makes identification of this common disease confusing to many clinicians. Also, with the varied manifestations of the disorder a patient may present to any one of several providers: an internist, family practitioner, nurse practitioner, pediatrician, gynecologist, dermatologist, or endocrinologist. Furthermore, the most distressing aspect of PCOS for any given patient may change over time, from hirsutism as a teenager to infertility as a young adult--potentially requiring several different providers along the way. It is important, therefore, that those caring for these patients understand not only the management issues pertinent to their specialty, but also appreciate the other potential health risks in these women. Recent insights into the pathophysiology of PCOS have shown insulin resistance to play a substantial role and as such have brought the long-term issues of type 2 diabetes mellitus and its resultant increased risk of coronary artery disease to the forefront. No longer can irregular menses and/or hirsutism be thought of as benign nuisances. This review will focus on the two most confusing aspects of PCOS for the practicing provider--diagnosis/differential diagnosis and treatment options. Special attention is given to the role of insulin resistance and the potential utility of insulin sensitizers in management. The benefit and utmost importance of lifestyle modification for the long-term health of these women is stressed as well. It is hoped that some clarity in this regard will allow more women to not only be diagnosed and managed properly for their presenting symptoms (hirsutism, irregular menses, etc.), but also to be educated and managed for the continuing health risk of insulin resistance throughout their lives.

Current therapeutic options in type 2 diabetes mellitus: a practical approach.

The incidence of type 2 diabetes mellitus (DM) in the United States continues to grow rapidly, paralleling the overweight and obesity epidemic. For many years the only therapeutic options for type 2 DM were sulfonylureas and insulin. However, over the last 9 years there has been an explosion of new and exciting agents approved for the treatment of type 2 DM. Some of the treatments target insulin deficiency and others insulin resistance, the hallmarks of the disease. Other drugs delay the intestinal absorption of carbohydrate. Recently several combination agents have been released. With these new drugs has come an overwhelming mountain of information, making it difficult for the busy clinician to know how best to manage the ever-increasing portion of patients with type 2 DM. New questions have arisen: Which agent to start as first line? How much of this drug to use before adding something else? How long for this drug to reach full effect? Which agent to add second? Should a patient uncontrolled on dual therapy begin insulin or start a third oral agent? If insulin therapy is started, what should become of the patient's oral agents? How best to explain the patient's weight gain on therapy? These are not easy questions and no review can fully detail all the therapeutic combinations possible. Instead, the practical approach of reviewing the agents in terms of their mechanism of action and critically comparing their dosing, effect and cost, is undertaken herein. Also addressed is the possible niche some newer classes of agents and combination drugs may or may not hold in the management of type 2 DM. The decision of using insulin versus a third oral agent will be looked at from the standpoint of where the patient is on dual therapy in relation to the hemoglobin A1c goal. In this way it is hoped that some clarity will be brought to the dizzying array of information that both the physician and patient have to deal with in regard to the management of this prevalent and serious disease.

Insulinoma in chronic renal failure: a case report.

The diagnosis of insulinoma depends on the fulfillment of well-established criteria during the 72-h fast. However, these criteria rely on normal renal function. Spontaneous hypoglycemia that is not attributable to insulinoma may occur in persons with renal failure. We describe herein a patient with renal impairment who had undergone renal transplant and had a 20-yr history of hypoglycemic symptoms and successful resection of insulinoma. Although the results of a 72-h fast were consistent with endogenous hyperinsulinemia, their interpretation was complicated in the presence of renal impairment. Fortunately, the identification of the tumor, by endoscopic ultrasonograph, led to a correct diagnosis. This case seems to be the second report of a patient with insulinoma with concomitant renal failure.