Abstract
Disclosure: E. Tirthani: None. F. Erenler: None.
Background: A proinsulinoma is a very rare neuroendocrine tumor of the pancreas, which predominantly secretes proinsulin, the precursor ...hormone of insulin. Even though not as potent as insulin, proinsulin in higher amounts can bind to insulin receptors and result in hypoglycemia. Most patients present with initial hypoglycemia symptoms at the time of diagnosis of the tumor. The diagnosis becomes challenging in patients with underlying type 2 diabetes mellitus (T2DM) who may initially have a spontaneous remission of diabetes, followed by hypoglycemia episodes later in the disease course. Clinical Case: A 66-year-old man presented to our clinic in October 2020 with frequent episodes of dizziness and diaphoresis, which were relieved by eating food. The patient's symptoms began in 2018, occurred during the daytime, and were exacerbated by exercise. He had a past medical history of T2DM diagnosed in 2009 (HbA1c=10%) and treated with glipizide and metformin; however, over the years, his HbA1c improved, and glipizide was discontinued. By 2018 his HbA1c was down to 5.9%, and metformin was also stopped. The patient denied any change in his weight, diet, or exercise frequency during this time course. A fingerstick blood glucose (BG) checked during one of these episodes was 51 mg/dL. An abdominal CT scan in August 2020 revealed a 12x13 mm enhancing mass within the neck of the pancreas concerning for a neuroendocrine tumor. The patient was further evaluated with a 14-day continuous glucose monitor (CGM), which showed that the patient's BG was <70 mg/dL 31% of the time and <55 mg/dL 6% of the time. Additional fasting blood work showed a proinsulin level of 191.3 pmol/L (normal ≤18 pmol/L), insulin 15.5 uIU/mL (2-25 uIU/mL), BG 103mg/dL, C-peptide 2.44 ng/mL (0.80-3.85 ng/mL) and chromogranin A 124 ng/mL (25-140 ng/mL) which suggested the diagnosis of proinsulinoma. A Gallium-DOTATATE scan showed a localized tumor within the pancreas with no metastasis. The patient underwent enucleation of the tumor in November 2020. Pathology showed a well-differentiated neuroendocrine tumor staged T1 pN0 with immunohistochemistry staining diffusely positive for chromogranin, synaptophysin, and insulin with a Ki67 index <3%. In January 2021, at a post-surgery follow-up visit, blood work showed HbA1c 7.1%, proinsulin 31 pmol/L, insulin 13.4 uIU/mL, C-peptide 1.6 ng/mL, BG 193 mg/dl, and chromogranin A 118 ng/mL. HbA1c continued to trend up to 8.0% in January 2022, confirming the resurgence of diabetes, and metformin and pioglitazone were started. Conclusion: Per our literature review, this is the first reported case of a proinsulinoma in a patient with T2DM. In a patient with uncontrolled T2DM, an unexpected amelioration of the disease should raise concern for insulin-secreting tumors, and further workup should be considered. A CGM can be a valuable tool to assess the severity of hypoglycemia in patients with these tumors.
Presentation: Saturday, June 17, 2023
Abstract
Background:
It is well known that delayed images from contrast-enhanced CT are useful in distinguishing adrenal adenomas from non-adenomas, with an absolute washout that exceeds 60% being ...most consistent with a lipid rich adenoma. We present two cases of an adrenal mass that met the criteria for a lipid rich adenoma by CT imaging, but found to be a pheochromocytoma (PCC) and paraganglioma (PGL).
Clinical Case
Case#1
An 82 yo woman presenting with tachycardia was found to have a 2.4 cm heterogeneously attenuating, left adrenal nodule with an absolute washout of 61% and a relative washout of 45%. The right adrenal was normal. Urinary catecholamine levels were elevated with an epinephrine (E) 38 mcg (2–24), norepinephrine (NE) 388 mcg (15–100), dopamine (DOPA) 175 mcg (52–480), metanephrine (MN) mcg 620 (90–315), normetanephrine (NMN) 1553 mcg (122–676) and vanillylmandelic acid 12.5 mg (< 6) on a 24h collection. Due to a cardiac resynchronization therapy device, an MRI could not be obtained. MIBG imaging was obtained and showed increased uptake in left adrenal gland, corresponding to the lesion identified on CT. The patient underwent laparoscopic adrenalectomy and the pathology confirmed a PCC.
Case#2:
A 74 yo man was found to have an incidental right adrenal nodule on CT imaging measuring 2.4 cm. Absolute washout was 83% and relative washout 68%. The left adrenal gland was normal. A follow up MRI obtained showed slight increase in T2 weighted images and no drop out on out of phase imaging, raising concern for a PCC. Urinary catecholamines were elevated including E 12 mcg (2–24), NE 280 mcg (15–100), DOPA 246 mcg (52–480), MN 175 mcg (90–315) and NMN 1298 mcg (122–676) on a 24-hr. collection. MIBG imaging further confirmed the diagnosis with increased uptake in the right adrenal gland. The patient underwent laparoscopic adrenalectomy then, converted to open right adrenalectomy through an anterior approach due to adherence of the tumor to the renal vein. The pathology revealed a PGL.
Conclusion:
PCC/PGL are rare but life-threatening neuroendocrine tumors that require early detection to reduce associated morbidities and mortality and improve surgical outcomes. CT is commonly used to characterize adrenal lesions and an absolute washout of >60% is most consistent with an adenoma. However, as demonstrated by these two cases, washout exceeding 60% can also be seen in non-adenomas, perhaps secondary to degeneration of the nodule causing necrotic or cystic changes or uncommonly, the presence of a high lipid content in the tumor 1. Thus, when clinical suspicion is strong and/or there is a positive biochemical workup, confirmatory imaging should be considered to establish the diagnosis.
References:
1 Blake, M. A., Kalra, M. K., Maher, M. M., Sahani, D. V., Sweeney, A. T., Mueller, P. R., ... & Boland, G. W. (2004). Pheochromocytoma: an imaging chameleon. Radiographics, 24(suppl_1), S87-S99.
Background
Chronic migraine has a well-documented association with increased insulin resistance and metabolic syndrome. The hypothalamus may play a role in the progression of insulin resistance in ...chronic migraine through the regulation of orexigenic peptides such as neuropeptide Y. Insulin resistance may lead to increased risk of future type 2 diabetes mellitus in patients with chronic migraine, which is more likely to occur if other pathogenetic defects of type 2 diabetes mellitus, such as impaired pancreatic β-cell functions and defects in intestinal glucagon-like peptide-1 secretion after meals. We studied the relationship of fasting neuropeptide Y with insulin resistance, β-cell function, and glucagon-like peptide-1 secretion in non-obese female chronic migraine patients. We also aimed to investigate glucose-stimulated insulin and glucagon-like peptide-1 secretions as early pathogenetic mechanisms responsible for the development of carbohydrate intolerance.
Methods
In this cross-sectional controlled study, 83 non-obese female migraine patients of reproductive age categorized as having episodic migraine or chronic migraine were included. The control group consisted of 36 healthy females. We studied glucose-stimulated insulin and glucagon-like peptide-1 secretion during a 75 g oral glucose tolerance test. We investigated the relationship of neuropeptide Y levels with insulin resistance and β-cell insulin secretion functions.
Results
Fasting glucose levels were significantly higher in migraine patients. Plasma glucose and insulin levels during the oral glucose tolerance test were otherwise similar in chronic migraine, episodic migraine and controls. Patients with chronic migraine were more insulin resistant than episodic migraine or controls (p = 0.048). Glucagon-like peptide-1 levels both at fasting and two hours after glucose intake were similar in chronic migraine, episodic migraine, and controls. Neuropeptide Y levels were higher in migraineurs. In chronic migraine, neuropeptide Y was positively correlated with fasting glucagon-like peptide-1 levels (r = 0.57, p = 0.04), but there was no correlation with insulin resistance (r = 0.49, p = 0.09) or β-cell function (r = 0.50, p = 0.07).
Discussion
Non-obese premenopausal female patients with chronic migraine have higher insulin resistance, but normal β-cell function is to compensate for the increased insulin demand during fasting and after glucose intake. Increased fasting neuropeptide Y levels in migraine may be a factor leading to increased insulin resistance by specific alterations in energy intake and activation of the sympathoadrenal system.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction: Glucocorticoids are commonly prescribed medications with a known side effect of hyperglycemia due to their effect on glucose metabolism. However, only 10-50% of patients receiving ...glucocorticoids develop overt hyperglycemia. It is unknown whether patients with increased genetic risk for type 2 diabetes (T2D) are predisposed to develop hyperglycemia after glucocorticoid treatment.
Methods: We accessed electronic health records and genetic data in the Mass General Brigham Biobank. We examined patients with no diagnosis of diabetes or prediabetes who received a glucocorticoid dose equivalent to 10 mg of prednisone or more, and who had glucose levels checked within 7 days of glucocorticoid administration. Hyperglycemia was defined as fasting blood glucose ≥126 mg/dL or random blood glucose ≥200 mg/dL. A T2D global extended polygenic score was constructed through a meta-analysis of T2D genome-wide association studies in the Million Veteran Program, DIAMANTE, and FinnGen. We performed logistic regression to analyze the association between the polygenic score and hyperglycemia, controlling for age, gender, BMI, baseline creatinine, glucocorticoid dose and duration, and the first 10 principal components of genetic ancestry.
Results: Out of 552 patients who received glucocorticoids, 216 developed hyperglycemia and 336 did not. The T2D polygenic score was significantly associated with glucocorticoid-induced hyperglycemia (p = 0.032, OR = 1.5 per standard deviation of the polygenic score). Other significant covariates included baseline creatinine (p = 8.0 × 10−4, OR = 2.2 per mg/dL of creatinine) and glucocorticoid dose (p = 9.5 × 10−5, OR = 1.01 per 10 mg of prednisone).
Conclusions: Patients carrying a higher burden of genetic variants that confer risk for T2D have an increased risk of hyperglycemia after receiving glucocorticoids. This finding offers a mechanism for risk stratification as part of a precision approach to medical treatment.
Disclosure
A.J.Deutsch: None. P.H.Schroeder: None. R.Mandla: None. F.Erenler: None. J.M.Mercader: None. M.Udler: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. L.Brenner: None.
Funding
National Institutes of Health (T32DK007028)
Abstract
Background
Immune checkpoint inhibitors (ICIs) in cancer treatment are considered one of the major breakthroughs in the past decade. Pembrolizumab (PBL) is one of the immune checkpoint ...inhibitors that targets the programmed cell death protein-1 (PD-1) receptor in order to block its interaction with programmed cell death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2). By inhibition of these molecules, PBL helps increase T-cell activation against cancer cells. Unfortunately, this inhibition also enhances autoimmunity against normal cells, leading to immune-related adverse events (irAEs) including endocrinopathies. Unlike other irAEs, endocrinopathies are usually irreversible upon diagnosis. While hypophysitis, hypo/hyperthyroidism, and adrenal insufficiency are more commonly reported, type 1 diabetes mellitus (T1DM) is also seen around 0.9 to 1.9% of cases. Unfortunately, it can become fatal if not being promptly recognized. To raise awareness about this life-threatening adverse event, we are reporting a case of new onset T1DM, presenting with diabetic ketoacidosis (DKA) only after 22 days of the first PBL infusion.
Clinical case
A 19-year-old male was recently diagnosed with NUT (nuclear protein in testis) carcinoma of the left floor of mouth with high PD-L1 score. NUT carcinoma is a rare type of squamous cell cancer with chromosomal rearrangement in the nuclear protein in testis gene (NUTM1) that makes the cancer aggressive and resistant to standard therapy, hence requiring a multimodal approach. This patient underwent surgery followed by concurrent cisplatin-radiation and PBL. Two weeks after his first PBL infusion, he suddenly developed polydipsia, polyuria, and nausea. He continued to receive the second PBL dose on day 20 and developed DKA on day 21. His work-up revealed a plasma glucose of 856 mg/dL, anion gap of 20 (H), CO2 of 17 mEq/L (L), and beta-hydroxybutyrate of 3.35 mmol/L (H), while hemoglobin A1C of only 5.5% suggesting his fulminant progression. He was immediately treated with DKA protocol with clinical improvement. The patient was discharged on basal bolus insulin regimen. He had non-detectable C-peptide (<0.10 ng/mL) and high GAD Antibody (>250 IU/mL) levels, which was consistent with PBL induced T1DM.
Conclusion
PBL use has been linked to multiple endocrinopathies and even though rare, DKA can also be seen in setting of T-cell mediated irreversible damage to pancreas beta cells. Due to life threatening potential of DKA, clinicians should monitor patients receiving immune checkpoint inhibitors closely and should be aware symptoms of hyperglycemia for earlier intervention. | Keywords: pembrolizumab, NUT carcinoma, diabetic ketoacidosis
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
To assess whether increased genetic risk of type 2 diabetes (T2D) is associated with the development of hyperglycemia after glucocorticoid treatment.
We performed a retrospective analysis of ...individuals with no diagnosis of diabetes who received a glucocorticoid dose of ≥10 mg prednisone. We analyzed the association between hyperglycemia and a T2D global extended polygenic score, which was constructed through a meta-analysis of two published genome-wide association studies.
Of 546 individuals who received glucocorticoids, 210 developed hyperglycemia and 336 did not. T2D polygenic score was significantly associated with glucocorticoid-induced hyperglycemia (odds ratio 1.4 per SD of polygenic score; P = 0.038).
Individuals with increased genetic risk of T2D have a higher risk of glucocorticoid-induced hyperglycemia. This finding offers a mechanism for risk stratification as part of a precision approach to medical treatment.
Abstract
Background: After surgical resection in adrenocortical carcinoma (ACC), mitotane is often used as adjuvant therapy. However, mitotane can cause adverse effects, such as inducing ...hypercholesterolemia by stimulating HMG-CoA reductase. In addition, mitotane is a strong CYP3A4 inducer which presents a challenge with statins, such as lovastatin, simvastatin, and atorvastatin. We present a case using a PCSK9 inhibitor in mitotane-induced hypercholesterolemia which was refractory to the maximum dose of rosuvastatin.
Clinical Case: A laparoscopic left adrenalectomy was performed on a 45-year old female with Stage 3 (T3, NX, M0) ACC (4.5 x 3.4 x 3.2 cm). Her ACC was determined to be high grade with a mitotic rate 20/50 HPF and Ki-67 of 18.7% with lymphovascular invasion and tumor invasion of periadrenal adipose tissue. Following surgical resection, she started adjuvant therapy mitotane and oral hydrocortisone replacement, as well as 6 weeks of radiation therapy. Prior to starting mitotane, her LDL-C was 133 mg/dL (normal range <130 mg/dL) and treated with simvastatin 40 mg daily. A drug interaction was identified between simvastatin and mitotane, with mitotane reducing effects of simvastatin via CYP3A4 induction, so rosuvastatin 10 mg daily was started instead. A trial of combination rosuvastatin and ezetimibe was used; however, patient discontinued ezetimibe due to reported side effects. As the dose of mitotane increased to achieve a blood concentration of 14–20 mcg/mL, LDL-C simultaneously increased along with a corresponding dose increase of rosuvastatin. While being on mitotane 2 g daily and rosuvastatin 40 mg daily, her lipids peaked with LDL-C 219 mg/dL. The decision was made to start evolocumab administered as 140 mg subcutaneously every 2 weeks in addition to rosuvastatin 40 mg daily. After 4 months of therapy with combination evolocumab and rosuvastatin, her LDL-C decreased to 111 mg/dL, a 49% reduction, while achieving a mitotane concentration of 13 mcg/mL using 4 g daily.
Conclusion: Utilizing a PCSK9 inhibitor, such as evolocumab, allows the dose of mitotane to be increased to achieve a therapeutic level while maintaining adequate control of cholesterol. With options for management of mitotane-induced hypercholesterolemia being limited, off-label use of a PCSK9 inhibitor can be justified clinically as moderate LDL-C reduction has also been shown in a prior published case report (1). Evolocumab is a well-tolerated subcutaneous injection, and should be considered for patients with resistant hypercholesterolemia while on mitotane.
References: (1) Tsakiridou ED, Liberopoulos E, Giotaki Z, et al. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor use in the management of resistant hypercholesterolemia induced by mitotane treatment for adrenocortical cancer. J Clin Lipidol. 2018;12(3):826–829.
Abstract
Purpose: To evaluate the effects of multiple intravitreal injections of ranibizumab on retinal nerve fiber layer (RNFL) thickness in patients with wet age-related macular degeneration (AMD).
...Methods: This observational, comparative study included patients with 10 or more total ranibizumab injections and involved the measurement of RNFL thickness at baseline. Twenty-nine eyes of 29 consecutive patients were evaluated via intraocular pressure (IOP) and measurements of the total and nasal RNFL thicknesses at the initial and final follow-up by using optical coherence tomography. The RNFL thickness values of the fellow eyes and 27 healthy eyes were used as the control group. The mean total and nasal RNFL thicknesses of the injection group were compared with those of the other two groups. At each visit, at every three injections, the IOP values of the study group were recorded and compared. The relationship between the number of injections and the mean RNFL thickness was assessed.
Results: The mean number of injections was 13.88 ± 3.81 (10-24). The mean RNFL thickness of the injection group was 92.3 ± 7.7 μm at baseline and 92.46 ± 8.1 μm at the last follow-up (p = 0.7). There were no statistically significant differences between the mean total and nasal RNFL thicknesses of the eyes with injections and the fellow eyes with no injections (p = 0.379, p = 0.897, respectively) or between those with injections and the healthy control group (p = 0.159, p = 0.273, respectively). There were no correlations between the number of injections and the mean total and nasal RNFL thicknesses (p = 0.854, p = 0.25, respectively). There was no statistical difference between the initial and final IOPs (p = 0.760).
Conclusion: Long-term treatment with anti-vascular endothelial growth factor (VEGF) agents did not lead to significant changes in RNFL thickness in a patient population with wet AMD. Chronic therapy with intravitreal anti-VEGF agents does not appear to adversely affect RNFL thickness.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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.
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.
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, α-adrenergic blockade therapy was associated with fewer adverse outcomes (3·6; 1·1-13·2 for no α-adrenergic blockade vs α-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0·9; 0·3-3·9 for no surgery vs surgery).
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.
US National Institutes of Health.
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