bluuebunny/crossref_metadata_2025 huggingface dataset:
Patients With Obesity-Related Hypertension Treated With Renin-Angiotensin-Aldosterone System Antagonists Exhibit Lower Mortality And Less Severe COVID-19: A Retrospective Study
Authors: Kamalumpundi Vijayvardhan , Shams Elham , Cheng Linhai , Taiwo Adeyinka , Shibli-Rahhal Amal A , Dokun Ayotunde O , Correia Marcelo
Published: May 2021

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been found to exploit the cell’s ACE2 receptor for viral entry. Renin-angiotensin-aldosterone system (RAAS) antagonism with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) increases the expression of ACE2 receptors which, coupled with the metabolic changes associated with obesity-related hypertension, can make hypertensive patients with obesity more vulnerable to severe COVID-19. Although current evidence suggests that ACEI/ARB use does not increase risk of severe COVID-19 in the general population, potential interactions with obesity-related hypertension are unknown. Methods: We conducted a retrospective study of COVID-19 patients admitted to the University of Iowa Hospitals and Clinics between March 1st and July 8th, 2020. We included adults who are overweight (BMI ≥ 25 kg/m2) or obese (BMI ≥ 30 kg/m2) with hypertension treated as outpatients with or without ACEIs/ARBs. Patients without exposure to RAAS antagonists served as controls. We assessed mortality and the severity of COVID-19 reflected by admission to ICU and usage of supplemental O2, non-invasive ventilation, mechanical ventilation, extracorporeal membrane oxygenation (ECMO) and vasopressors. Results: Of the 369 inpatients with COVID-19, we identified 138 exhibiting obesity-related hypertension who were then allocated into the control (n=59) and ACEI/ARB (n=79) groups. The BMIs between groups at baseline were not statistically significant (Control: 33.6 ± 0.96 vs. ACEI/ARB: 34.99 ± 0.97; p=.32). Women were less represented in the ACEI/ARB group (Control: 47% vs. ACEI/ARB: 24%). The controls had a substantially higher mortality rate (Control: 32.2% vs. ACEI/ARB: 15.1%). In regard to the severity of COVID-19, the ACEI/ARB cohort showed lower usage of supplemental O2 (Control: 52.5% vs. ACEI/ARB: 49.3%), mechanical ventilation (Control: 37.2% vs. ACEI/ARB: 1.2%), vasopressors (Control: 38.9% vs. ACEI/ARB: 31.6%), and had lower ICU admissions (Control: 57.6% vs. ACEI/ARB: 46.8%). However, the ACEI/ARB group had higher rates of: ECMO (Control: 0% vs. ACEI/ARB: 20.2%) and non-invasive ventilation (Control: 18.6% vs. ACEI/ARB: 20.2%). Of note, the rate of diabetes was higher in the ACEI/ARB cohort (Control: 45.7% vs. ACEI/ARB: 63.2%). Conclusion: Our results suggest that a history of RAAS antagonism is associated with lower mortality and less severity of COVID-19 in patients with obesity-related hypertension requiring hospital admission.
Re-Evaluating Absent Clinical Success After Adrenalectomy in Unilateral Primary Aldosteronism
Authors: Puar Troy , Chan Yvonne , Loh Lih-Ming , Foo Roger , Kek Peng Chin
Published: May 2021

Introduction: Adrenalectomy cures unilateral primary aldosteronism (PA), and improves or cures hypertension. However, a significant proportion of patients are classified with absent clinical success post-surgery, suggesting that surgery was ineffective. Methods: We assessed all patients 6–12 months after unilateral adrenalectomy for clinical outcomes using Primary Aldosteronism Surgical Outcomes (PASO), AVIS-2 and CONNsortium criteria. We estimated blood pressure (BP) changes after adjustment for changes in defined daily dosages (DDD) of antihypertensive medications. Finally, patients were reassessed using PASO at their most recent clinical visit. Results: 104 patients with unilateral PA underwent adrenalectomy at two tertiary centres from 2000–2019. 24 (23%), 31(30%) and 54 (52%) patients were classified with absent clinical success using PASO, AVIS-2 and CONNsortium criteria respectively. Amongst 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 multivariate analysis, absent clinical success was associated with presence of hyperlipidemia, diabetes mellitus and lower DDD at baseline. After adjustment for changes in DDD, 7 of 24 patients showed BP improvement ≥20/10mmHg. After 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 any clinical improvement after surgery. Conclusions: Although some patients may be classified with absent clinical success post-surgery, majority demonstrate evidence of clinical benefit. Unilateral adrenalectomy remains the recommended treatment option for patients with unilateral PA.
The Spatial Epidemiology of Patients Who Were Screened for and Diagnosed With Primary Aldosteronism in Southern Thailand
Authors: Suntornlohanakul Onnicha , Kietsiriroje Noppadol , Sakarin Suporn , Sriplung Hutcha
Published: May 2021

Background: In Thailand where biochemical testing for detection of primary aldosteronism (PA) is only available in a few tertiary centers, which may contribute to a delay in case detection. This study aimed to identify the geographic distribution of PA screening and diagnosis and its contributing epidemiologic and geographic factors in Southern Thailand. Method: Data of 688 patients who underwent PA screening between 2011–2017 were reviewed from the electronic database. The patients’ residences were extracted from the identification cards or the address recorded in the hospital system. The presence of an endocrinologist and the dominant religion in each province were recorded. The province, district and subdistrict of each patient were transformed to a 6-digit administrative area code corresponding with the global one (GADM©). A generalized log-linear model was used to identify predictors for individuals being screened. Results: Overall, the prevalence and crude incidence rates of PA in Southern Thailand were 15.6% and 1.66/1,000,000 person-years, respectively. The provinces located adjacent to the Andaman Sea had the highest incidences of PA (3.62–5.17 patients/1,000,000 person-years). Areas with the highest screening rates were located at and near Songkhla where the major tertiary medical center is located. A multivariate log-linear model demonstrated that the distance from the major tertiary center was the only predictive factor for screening while the availability of an endocrinologist and cultural differences were not. The chances of patients who lived in Songkhla, lived less than or more than 200 km from Songkhla to receive PA screening were 100% (reference), 82% (95% CI:0.69–0.97, p-value 0.03), and 66% (95% CI:0.55–0.78, p-value < 0.001), respectively. Conclusion: Geographic location was the main factor contributing to a delay in case detection for PA. A public health policy should be developed to mitigate the geographic barrier thus improving the ability of patients to access healthcare services. Further research relating to the underlying risk of the disease such as genetic transmission in populations with a high incidence of PA should be performed.
Time-Varying Risk of Atrial Fibrillation in Patient With Medically and Surgically Treated Primary Aldosteronism: A Nationwide Cohort Study
Authors: Kim Kyoung Jin , Hong Namki , Lee Seunghyun , Rhee Yumie , Lim Jung Soo
Published: May 2021

Evidence of increased cardiovascular risk, especially atrial fibrillation, has been accumulating among patients with primary aldosteronism (PA), but there is still limited information about long-term prognosis related to different treatment strategy. The aim of this study was not only to investigate the incidence of atrial fibrillation, but also to evaluate their time-dependent changes after adrenalectomy (surgery group) or mineralocorticoid receptor antagonists (drug group) for patients with PA compared to those with essential hypertension (EH). From a nationwide cohort in Korea (2003–2017), PA were individually matched for sex, age (±10 years), and index year in a 1:5 ratio with EH. The primary end point was the time-varying risk of new-onset atrial fibrillation (NOAF) among PA according to treatment mode compared to EH. The secondary end points were the risks of major adverse cardiovascular events (composite of non-fatal myocardial infarction, non-fatal stroke, and death from cardiovascular causes), hospitalization for heart failure, and all-cause mortality. Cox proportional-hazards analysis or time-dependent Cox analysis based on the Schoenfeld residuals testing were performed. We enrolled 1,418 PA patients (755 in PA surgery group and 663 in PA drug group), and matched theses with 7,090 EH controls with a median of 5 years. The risk of incident NOAF was statistically higher in patients with PA (both surgery and drug groups) within the three years after diagnosis (adjusted hazard ratio, 3.02; p<0.001), whereas there was no statistically significance after the three years compared to EH (adjusted hazard ratio, 0.50; p=0.053). Patients in the PA drug group had higher risk of non-fatal stroke during the total followed up period (adjusted hazard ratio, 1.53, p=0.031), although the PA surgery group didn’t. In contrast, patients with PA had no statistically significant difference in risks for other secondary cardiovascular outcomes. In conclusion, this propensity cohort study of adults with PA demonstrated the changeable risk of NOAF over time possibly due to the residual effect of inappropriate aldosterone levels. These findings can provide clinically relevant guidance in the

monitoring the cardiovascular complications, especially NOAF and non-fatal stroke, even after treatment among patients with PA.

Acknowledgements: This study was supported by Collaborative Research Project of Korean Endocrine Society and National Health Insurance Sharing Service (NHIS-2019-4-005). We also thank Minheui Yu and Doori Cho, the members of the SENTINEL (Severance ENdocrinology daTa scIeNcE pLatform) team for technical assistance in searching and summarizing the relevant literature (4-2018-1215).
Utility of Plasma Metanephrines in Adrenal Venous Sampling in Primary Aldosteronism
Authors: Sharma Aditi , Mohsin Zaineb Amin , Moore-Gillon Claudia , Derry Joseph , Thomas Kate , Whitlock Matthew , Williams Emma Louise , Barnes Sophie , Palazzo Fausto , Alsafi Ali , Wernig Florian
Published: May 2021

Introduction: Adrenal Venous Sampling (AVS) is the most reliable means of identifying surgically curable subtypes of primary aldosteronism (PA). Cortisol levels are used to determine cannulation success and lateralization. However, cortisol has a variable secretion pattern and long-half life, and can be co-secreted by adrenal adenomas, leading to misinterpretation of results. Plasma metanephrines (MN) are a possible alternative analyte. MN levels are unaffected by stress, have a short half-life of 3–6 minutes and are released continuously by the adrenals, resulting in very high concentration gradients between the adrenal veins (AV) and peripheral veins (PV), thus providing a sensitive means to determine cannulation success. Premise:The objective of this study was to see if MN can be used in lieu of cortisol in AVS. A secondary end-point was to see if the data was particularly useful in patients who are known co-secretors of cortisol. Methods: Data from AVS carried out without cosyntropin stimulation, from October 2018 to March 2020, were analysed retrospectively. Of these, 51 had additional samples drawn for MN at the time of the procedure and were recruited. Six patients were identified as having autonomous cortisol secretion as they failed an overnight dexamethasone suppression test (ONDST). The data was analysed using cortisol and MN separately and then compared with regards to their selectivity and lateralization index. Data was also analysed to see if known co-secretors had an elevated cortisol/MN ratio of more than 2 on the affected side as described in previous papers. Results: When compared to cannulation and lateralization outcomes using cortisol, similar results were obtained using, a MN AV/PV ratio of more than 12 to indicate successful cannulation and an aldosterone/MN ratios of greater than 5 to confirm lateralization. Contralateral suppression to less than 0.5 for aldosterone/MN below the PV was seen in unilateral disease. With regards to the six co-secretors, all had elevated cortisol/MN ratios of more than 2 on the affected side. Three had concordant results but the other three had discrepant results, with MN analysis suggesting unilateral disease and cortisol measurements suggesting bilateral disease. Two had undergone surgery with biopsy confirming unilateral disease that correlated with MN analysis. The third is under medical management. Conclusion: This is the first study evaluating the use of MN to determine lateralisation of aldosterone production in PA. Further studies are needed, but using MN may be a more reliable alternative to cortisol in the analysis of AVS before definitive surgery in particular in patients with cortisol co-secretion.
A Case of Hypolipidemia and Hypocholesterolemia; Cause and Consequences
Authors: West William A , Romo Karina , Zaidi Raza , Hoard Brandon , Uwaifo Gabriel Ikponmosa
Published: May 2021

Background: Hypolipidemia and hypocholesterolemia are uncommon and because of the established risk of hypercholesterolemia for cardiovascular disease, reduced lipids and total cholesterol levels are often clinically desired and/or deemed clinically inconsequential. A finding of persistently low lipid levels and total cholesterol may however not be innocuous nor desirable. We describe the case of a 46 yr old man with persistently low total cholesterol levels <70mg/dl and the associated complications and comorbidities identified. Clinical Case: A 46 yr old Hispanic man with non-alcoholic fatty liver disease (NAFLD) was referred for evaluation of hyperhidrosis in the setting of persistent hypolipidemia and hypocholesterolemia. Review of the patient’s clinical and biochemical history showed persistently low total cholesterol (mean 58mg/dl), hypotriglyceridemia, and low LDL-C (mean 13.4mg/dl) over the prior 7 yrs in addition to undetectable serum lipoprotein A. Evaluation for secondary causes of hypolipidemia, such as multiple myeloma, was unremarkable. He was found to have low carotene, borderline vitamin A and low vitamin E levels while the rest of his serum fat-soluble vitamins were normal. His mother who had presumed Alzheimer’s dementia also had a history of very low cholesterol levels. The degree and persistence of his hypolipidemia and hypocholesterolemia raised the possibility of a genetic etiology of his hypolipidemia. Genetic testing confirmed that the patient was heterozygous for a pathogenic variant in the APOB gene, consistent with familial hypobetalipoproteinemia (FHBL) which is autosomal recessive linked. Subsequent close review of his clinical history revealed other potential complications and comorbidities of FHBL including NAFLD with prediabetes, hypogonadism, progressive cognitive and memory decline, peripheral neuropathy and multiple neuropsychiatric syndromes including adult ADHD, borderline personality disorder, bipolar disorder and chronic anxiety. He is presently on vitamin E and A supplementation and being followed by neurology and psychiatry in addition to ongoing endocrine and metabolic clinical surveillance. In addition, in view of his maternal history and several biologic children he has undergone formal genetic and family counselling. Conclusions: While lipid panels are ubiquitous in clinical care, clinicians need to be vigilant in settings of severe persistent hypolipidemia and/or hypocholesterolemia to evaluate for possible genetic basis for this and to also screen for possible associated complications and comorbidities.
Diet-Responsive Hypercholesterolemia With Cardiofaciocutaneous Syndrome Type 3
Authors: Patni Nivedita , Garg Abhimanyu , Xing Chao
Published: May 2021

Background: Molecular basis of diet responsive hypercholesterolemia remains unclear. We report diet-responsive severe hypercholesterolemia in a young female with cardiofaciocutaneous syndrome type 3 (CFC3) due to a heterozygous pathogenic MAP2K1 variant, suggesting a role of common MAPK variants in LDL-cholesterol (LDL-C) response to diet. Clinical case: A 3-year-old Caucasian female with CFC3 (macrocephaly, frontal bossing, wide nasal root with depressed bridge, anteverted nares, low set fleshy ears, congenital pulmonic valve stenosis, postnatal growth deficiency, hypotonia, and neurocognitive impairment) due to a de novo heterozygous c.389A>G, p.Tyr130Cys pathogenic variant in MAP2K1, presented with extremely elevated serum total cholesterol of 446 mg/dL, triglycerides of 239 mg/dL, HDL-cholesterol of 53 mg/dL, LDL-C of 335 mg/dL (normal range < 110 mg/dL) and serum apolipoprotein B level 219 mg/dL (normal range < 90 mg/dL). Her LDL-C was 252 mg/dL a year ago and 215 mg/dL one month prior to presentation. Reducing total dietary fat to 20–25% of total energy and saturated fat to <6% of total energy over the next 4 months lowered LDL-C to 104 mg/dL. However, her weight decreased by 0.5 kg and liberalization of fat intake again increased LDL-C to 222 mg/dL. Her father has mildly elevated LDL-C of 160 mg/dL and her mother had normal LDL-C of 80 mg/dL. Her plasma phytosterol levels were normal and she had ApoE3/E3 genotype. Targeted genetic testing of the patient and parents showed a benign heterozygous LDL receptor (LDLR) variant c.2242G>A; p.Asp748Asn, (Minor allele frequency 0.00008) in the patient and her father. Whole exome sequencing of the patient and both parents showed no known disease-causing variants in LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, LIPA, ABCG5, ABCG8 and other known hyperlipidemia-related genes. There are no previous reports of hypercholesterolemia in patients with CFC3. MAP2K1 stimulates various MAP kinases upon wide variety of extra- and intracellular signal and is involved in cell proliferation, differentiation, transcription regulation and development. Previous studies of the relationship between p42/44MAPK activation and LDLR expression in human hepatoma HepG2-derived cell line showed that that activation of the Raf-1/MEK/p42/44MAPK cascade induces LDLR expression and modulation of the Raf-1 kinase signal strength can determine LDLR expression levels. Thus, extent of MAPK activation can alter signaling of LDLR, resulting in hypercholesterolemia. Conclusion: Our case report suggests that MAP2K1 may play a significant role in LDLR signaling, and some MAP2K1 variants may be associated with diet-responsive hypercholesterolemia. Larger studies are required to assess dietary response to LDL-C in subjects with MAP2K1 variants.
Fluphenazine-Induced Severe Hypertriglyceridemia
Authors: Taneja Charit , Beuttler Marc , Thavaraputta Subhanudh
Published: May 2021

Introduction: Antipsychotics are known to result in lipid dysregulation, possibly through their effects on weight, appetite and increased glucose intolerance. These effects are seen in varying degrees with both typical and atypical antipsychotics. This results in a cohort of patients with drug-induced hyperlipidemia, who benefit from lipid-lowering therapy. We describe an extreme scenario where the use of fluphenazine resulted in very severe hypertriglyceridemia, in addition to new onset diabetes requiring inpatient management.

Case: A 42-year-old man with schizophrenia and a history of mild hypertriglyceridemia presented to the emergency department with one month of polyuria and polydipsia, and a home glucose measurement of >500 mg/dL. Six months earlier, he had been started on fluphenazine for schizophrenia. Laboratory testing at that time showed Hemoglobin A1c of 6.0% and a mild elevation in triglycerides to 188 mg/dL. He endorsed a family history of hypertriglyceridemia and type two diabetes. On physical exam, he appeared healthy with no abnormal focal findings. Labs revealed Hemoglobin A1c of 14% and a triglyceride level of 15,213 mg/dL. His blood samples became rapidly lipemic within a few minutes of the blood draw, corrupting the majority of the lab values. He was admitted to the ICU for continuous IV insulin, which improved his severe hypertriglyceridemia over the course of one week. Fluphenazine was switched to ziprasidone for schizophrenia. Pancreatic autoimmune workup was negative. Once the patient’s triglyceride level was <1000 mg/dL, insulin drip was discontinued and gemfibrozil was started. His triglyceride level at discharge was 449 mg/dL, and decreased to within the normal range over the course of a few months at outpatient follow up.

Discussion: The highest on the differential for this case is fluphenazine-associated worsening of pre-existing hypertriglyceridemia in a patient with risk factors for metabolic syndrome. Antipsychotics can result in new-onset or worsening of metabolic syndrome. These patients can usually be managed in the outpatient setting with lipid-lowering therapies and glycemic control. This case represents a rare scenario of a dramatic hypertryglyceridemia and worsening of diabetes secondary to the use of the typical antipsychotic fluphenazine.
Hypertriglyceridemia-Induced Pancreatitis
Authors: Mung Sai Man , Jude Edward
Published: May 2021

A 31-year-old woman was admitted with abdominal pain. Her blood sample was noted to be lipemic. She was not known to have diabetes, hypothyroidism or family history of hyperlipidaemia and denied alcohol intake. She had no eruptive xanthoma or corneal arcus. On admission, triglycerides were 118mmol/L (normal range < 1.8). Computed tomographic scan demonstrated swollen pancreas, extensive peripancreatic inflammation and fatty liver. A diagnosis of hypertriglyceridemia-induced pancreatitis was made.

She was kept nil by mouth and commenced on insulin infusion, fenofibrate and a low-fat diet. Her admission was complicated by acute respiratory distress syndrome and difficult pain control requiring morphine patient-controlled analgesia. Her triglycerides gradually reduced and on day 12 it was 6.6mmol/L.

This case illustrates the importance of multidisciplinary input with endocrinologist, intensivist, gastroenterologist and dietician. Other treatments that could have been initiated was plasma apheresis but as she improved this was not required.
Importance of Diet Modification in Preventing Recurrent Episodes of Hypertriglyceridemic Pancreatitis (HTGP)
Authors: Janakiram Nikhila
Published: May 2021

Background: Hypertriglyceridemic pancreatitis (HTGP) typically occurs in patients with an underlying dyslipidemia. While the incidence is low (2–4%), HTGP has a higher likelihood of recurrence than other forms of pancreatitis. A multifaceted approach is necessary to prevent recurrences of HTGP. Diet modification is an integral part of management, but is usually not well emphasized in this patient population.

Clinical Case: A 22 year old male with hx of recurrent pancreatitis due to familial hypertriglyceridemia presented to the emergency department with epigastric pain beginning on morning of admission. The patient’s 1st pancreatitis episode was 1 year ago and he had 8 incidences of pancreatitis due to elevated triglyceride levels. One episode required ICU stay due to pressor requirement. Patient noted medication compliance to gemfibrozil since this admission, however stated that he had not made any changes in his diet since diagnosis 1 year ago. Patient had been abstinent from alcohol and drugs 6 months prior to admission. Patient’s triglyceride level on admission was 1,203 and was started on insulin drip. However, due to persistent hypoglycemia was also placed on D5 mIVFs. Despite the fluids, patient continued to be hypoglycemic and insulin drip was stopped for a short period of time with the triglyceride level in the 700s. The following night, patient was placed back on insulin drip at higher rate and became hypoglycemic again. Consequently, insulin drip was turned off the following morning. Triglyceride level continued to downtrend to 510. Insulin drip was restarted at a lower rate later that day. A recheck of triglyceride level that day showed that triglyceride decreased to 470. Patient was placed back on gemfibrozil with niacin added to the regimen and discharged home after a detailed discussion about diet changes.

Discussion: This case study illustrates a patient with multiple episodes of pancreatitis due to elevated triglyceride levels despite compliance to gemfibrozil, resulting in refractory hypoglycemic episodes during his most recent admission from chronic damage to the pancreas’s alpha cell activity. While medication compliance is important, diet modification is as well. The above case sheds light on the importance of long-term diet modification in patients including restriction of dietary fat, simple carbohydrates and alcohol.
The Importance of Ophthalmic Examination in Initial Diagnostic Process of Xanthoma: Two Case Reports and Literature Review of Cerebrotendinous Xanthomatosis
Authors: Goak Insun , Jang Seol A , Park Ji Hyun
Published: May 2021

Background: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease where deficiency of sterol 27-hydroxylase leads to reduced production of CDCA. In such cases, life expectancy is only 4–6 decades, with progressive neurologic dysfunction such as dementia and spinal cord paresis, unless the condition is diagnosed early and treated appropriately. Herein, we aim to raise awareness regarding the importance of ophthalmic examination in evaluating of xanthoma. Clinical Cases: Case 1: In a 58-year-old man with no neurological symptoms; bilateral cataracts were detected during the initial diagnostic process. This patient had two siblings with xanthoma; one died from cerebral infarction and the other from biliary tract cancer. Another sibling had premature acute cardiovascular disease without xanthomas. Baseline lipid profiles were nearly within the normal range, while lipoprotein A was approximately 2.5 times higher than the normal. CTX was confirmed by the detection of a homozygous mutation in the CYP27A1 gene and high plasma cholestanol level (8.5 mg/L; reference range 0.0–5.0 mg/L). He has been taking oral CDCA (250 mg, three times daily). Case 2: In a 24-year-old man with no neurological symptoms or intellectual disability, premature bilateral cataracts were detected 1 year prior to diagnosis of CTX. None of his family members had xanthoma or premature cardiovascular disease. Lipid profile showed a similar pattern to that of Case 1; CTX was confirmed by the detection of a homozygous mutation in the CYP27A1 gene and high plasma cholestanol level (21.33 mg/L). One year after starting CDCA (250 mg, three times daily), cholestanol levels dropped to 7.34 mg/L. They were measured annually and identified as 5.08 mg/L, 4.2 mg/L, 4.7 mg/L, and 3.8 mg/L at 24, 38, 61, and 72 months, respectively. It took approximately 2 years for the normalization of his cholestanol level. There were no recurrences of xanthoma or progression of complications in target organs after 6 years of treatment. Conclusion: Early diagnosis improves the outcomes of CTX, allowing proper treatment. Bilateral cataracts caused by cholestanol buildup on the crystalline lens due to CTX usually occur within the first three decades of life. This manifestation does not occur in patients with xanthoma, familial hypercholesterolemia, or sitosterolemia. Taken together, this report suggests that premature bilateral cataracts are a specific marker that can accelerate early diagnosis of CTX. References: (1) Duell PB et al. Diagnosis, Treatment and Clinical Outcomes in 43 Cases with CTX. Journal of Clinical Lipidology. 2018;12:1169 (2) Salen G, Steiner RD. Epidemiology, diagnosis, and treatment of CTX. J Inherit Metab Dis 2017: 40:771
Two Cases of Statin Induced Necrotizing Autoimmune Myopathy
Authors: Alam Mustafa , Asad Omar , Lababidi Hashim , Alam Mahad , Shahlapour Mahmoud , Horani Mohamad Hosam
Published: May 2021

Case 1: Six months ago, patient 1 presented with rhabdomyolysis with a CK of 17,622 Units/L. The statin was discontinued at that time, after which the patient noted substantial improvement in muscle symptoms. Two months later the patient was readmitted for complaints related to continued rhabdomyolysis. CK was elevated at 9800 Units/L, raising suspicion for SINAM. Physical exam findings on readmission were pertinent for 4/5 strength in proximal flexion and extension of the upper extremities bilaterally and 4/5 strength in hip flexion. Pertinent lab values on readmission include increased ALT of 122 Units/L, AST of 103 Units/L, TSH of 7.4 mIU/L, HbA1c of 6.6%, and BUN of 14.5 mg/dL. Urinalysis is positive 3+ for glucose, 1+ for ketones, and 2+ for blood. Brain MRI without contrast negative for any brain malignancies or abnormalities. Case 2: Patient 2 presented with gradual proximal muscle weakness while taking a statin for the past six months. Physical exam was notable for 4/5 strength in the biceps and triceps and 3/5 deltoid strength bilaterally. There was 4/5 strength in the knee flexors and extensors with 3/5 strength in the hip flexors bilaterally. Notable lab values include CK of 10,449 Units/L, CK-MB of 492ng/mL, fasting glucose of 160 mg/dL, ALT of 229 Units/L, and HgbA1C of 7.3%. Urinalysis was positive 3+ for glucose, 1+ for ketones, and 2+ for blood. Discussion: Statin induced necrotizing autoimmune myopathy (SINAM) is a rare complication of statin therapy in which subjects develop an immune response to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). SINAM’s pathophysiology remains poorly understood. Studies have shown that statins upregulate expression of HMGCR which serve as antibody targets in SINAM (Mohassel & Mammen, 2013). The HMGCR protein is upregulated in regenerating muscle fibers thus preferentially allowing autoantibodies to bind (Mammen et al, 2011). Additionally, complement is implicated in pathogenicity of SINAM with a study showing that C3 deficient mice had less pronounced deficiency in muscle strength (Bergua et al, 2019). This is further reinforced with a muscle biopsy in another SINAM confirmed patient showed C5b-9 sarcolemmal deposits (Sharma et al, 2019). This implicates the formation of antigen-antibody-complement complexes typical of a type III hypersensitivity reaction. Additionally, genetic risk factors for autoimmunity are important to consider. There is an association of SINAM occurrence in individuals with single nucleotide polymorphism in the SLCO1B1 that regulates hepatic uptake of drugs such as statins (SEARCH, 2008). HLA- DRB1*11:01 is associated with the formation of autoantibodies in SINAM (Mammen, 2016). Recent studies show the triple induction therapy of steroids, IVIG, and a steroid sparing immunosuppressant has been very effective (Meyer et al, 2020).
The Impact of ACTH on Peripheral Steroids Differs between Unilateral and Bilateral Primary Aldosteronism
Authors: Tezuka Yuta , Ishii Kae , Zhao Lili , Yamazaki Yuto , Morimoto Ryo , Sasano Hironobu , Udager Aaron , Satoh Fumitoshi , Turcu Adina
Published: May 2021

Background: ACTH is thought to contribute to aldosterone excess in primary aldosteronism (PA), possibly via aberrant melanocortin type 2 receptor (MC2R) expression in aldosterone producing adenomas (APAs). Dynamic manipulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a non-invasive tool for distinguishing unilateral PA (UPA) from bilateral PA (BPA), but existing data are minimal. Objective: To characterize the steroid responses to intrinsic ACTH variations and extrinsic HPA manipulation in UPA and BPA. Methods: We conducted comprehensive dynamic testing in PA patients, who were subtyped based on adrenal vein sampling. Peripheral plasma samples were collected from each patient at 6 time-points: morning; midnight; after 1 mg dexamethasone suppression (DST); and after cosyntropin stimulation (at 15’, 30’, and 60’). We quantified 15 steroids by mass spectrometry in each sample. Next generation sequencing was used to detect aldosterone-driver somatic mutations in APAs from 39 cases with available tissue. The Mann-Whitney test, Wilcoxon signed rank test, and repeated measures two-way ANOVA were employed, as appropriate. Penalized logistic regression was used to select steroids that best distinguished UPA from BPA. Receiver operating characteristic (ROC) curves were then plotted using the predicted score from the logistic regression model with the selected steroids, and area under the curves (AUC) were computed. Results: We included 80 PA patients, median age 51 (range, 26–76), 50% men, 40 with each subtype, both groups with similar age and sex distribution. Morning and midnight concentrations of 18-hydroxycortisol (18OHF), 18-oxocortisol (18oxoF), aldosterone, and 18-hydroxycorticosterone (18OHB) were higher in patients with UPA vs. BPA (p<0.001 for all). In response to cosyntropin stimulation, the UPA group had larger increments of aldosterone, 18oxoF, 11-deoxycorticosterone, corticosterone, and 11-deoxycortisol than the BPA group (p<0.05 for all). Following DST, aldosterone,18OHF, and 18oxoF were higher in UPA than in BPA patients (p<0.01 for all). Overall, cortisol and cortisone serum concentrations were similar between the two subtypes. Of the UPA cases, 27 (69%) had KCNJ5 mutations. Relative to UPA patients with other mutations, the KCNJ5 group had higher 18oxoF and 18OHF at baseline; higher 18oxoF and corticosterone after both dynamic tests; and lower aldosterone after DST. The highest AUC for PA subtyping was achieved using cosyntropin stimulated steroids (0.957), while baseline data reached an AUC of 0.909. Conclusions: Steroid responses to dynamic HPA testing differs between UPA and BPA: 18oxoF and 18OHF are less suppressible, while several steroids are disproportionally amplified by ACTH in patients with UPA vs. BPA. Such non-invasive tests could circumvent the need for adrenal vein sampling in a subset of PA patients.
AZP-3404, a Peptide Analog of IGFBP-2, Induces Weight Loss and Improves Glucose Metabolism in Leptin-Resistant db/db Mice
Authors: Culler Michael D , Milano Stéphane , Delale Thomas , Ovize Michel , van der Lelij Aart Jan , Clemmons David R
Published: May 2021

Insulin-like growth factor binding protein-2 (IGFBP-2) has been demonstrated to be a key mediator of the peripheral metabolic actions of leptin. The metabolic activity of IGFBP-2 is independent of IGF1 binding, and can be localized to a unique heparin-binding domain (HBD-1) within its structure. AZP-3404 is a 9-amino acid analog of the IGFBP-2 HBD-1 that reproduces the activity of IGFBP-2 on adipocyte and osteoblast differentiation. In addition, AZP-3404 has been demonstrated to increase glucose uptake by differentiated mouse myotubes in vitro, and to increase glucose disposal following an intraperitoneal glucose tolerance test (IPGTT) in leptin-deficient ob/ob mice. In the present study, we hypothesized that AZP-3404 should be able to improve metabolic regulation in the db/db mouse, which is leptin-resistant due to a mutation in the leptin receptor, and, as a result, is also IGFBP-2 deficient. Following pre-treatment with vehicle for 1 week to establish a baseline, 9-week old male db/db mice were treated with either vehicle or AZP-3404 at doses of 1, 3 or 6 mg/kg, sc, bid (n=10/group) for 8 weeks. At the initiation of treatment, the mice weighed an average of 39.7 + 0.3 grams, and after 8 weeks, vehicle-treated mice had gained an average 8.2 + 1.6 grams of body weight. Mice treated with AZP-3404 displayed a progressive decrease in body weight gain that began after 2 weeks and that continued through the 8 weeks of treatment, ultimately resulting in less than 50% of the weight gain observed in the vehicle-treated mice, and without an apparent change in food intake. To assess the impact on glucose disposal, after both 4 and 8 weeks of treatment, and following an overnight fast, the mice were administered an IPGTT (blood glucose measured 0, 30, 60, 90, 120 and 240 minutes post-ip injection of 1 g glucose/kg). By 4 weeks of treatment, a significant increase in glucose disposal was observed in mice treated with the 6 mg/kg dose of AZP-3404 (AUC glucose decreased by 28.7%) versus vehicle-treated controls. By 8 weeks of treatment, all three doses produced similar increases in glucose disposal (AUC glucose decreased by 18.8, 21.4 and 23.1% with 1, 3 and 6 mg/kg AZP-3404, respectively) versus vehicle controls. Correspondingly, 4-hour fasted plasma insulin was decreased by 54, 48 and 52%, and the HOMA measure of insulin resistance was decreased by 55, 52 and 67%, in mice treated for 8 weeks with 1, 3 and 6 mg/kg AZP-3404, respectively, as compared with vehicle-treated mice. These results, demonstrating both improved glucose metabolism and decreased body weight gain in the leptin-resistant db/db mouse, further confirm the ability of AZP-3404 to reproduce the metabolic activity of IGFBP-2, and support the development of AZP-3404 as a novel therapy for disease states characterized by insulin resistance and/or obesity.
Functional Heterogeneity Among Pancreatic Alpha Cells
Authors: Noguchi Glyn M , Ou Rosie , Castillo Vincent , Donaldson Cynthia J , Mawla Alexander M , Huising Mark O
Published: May 2021

Historically, endocrine cells in the pancreatic islets have been assumed to function as relatively homogenous populations largely because we lacked the ability to measure individual cell activity with sufficient throughput to reliably detect heterogeneity within each population. The glucagon-secreting alpha cells play a vital role in regulating glycemia, but the mechanisms that control alpha cell activity and whether the alpha cells behave as a single unit or heterogeneously remain incompletely understood. To overcome the limitations in throughput that have to date prevented the study of alpha cells at the population level, we used genetically-encoded fluorescent indicators selectively expressed in alpha cells. Imaging intact mouse islets with these indicators in 3D responding to treatments in real time yields hundreds of individual alpha cell recordings per experiment. Calcium imaging showed reproducible heterogeneous responses to a panel of known physiological potentiators of glucagon secretion such as arginine vasopressin, epinephrine, and amino acids. Separate dose response experiments revealed that the proportion of alpha cells responding to each signal plateaus at different proportions of alpha cells. The calcium data correlate both with direct glucagon secretion levels as well as cAMP measurement. Our findings highlight previously unappreciated levels of functional heterogeneity among alpha cells and demonstrate that alpha cells are not a single uniform unit. Our observations suggest that dose-dependent increases in glucagon secretion in response to different physiological cues may be the result of mobilizing progressively larger proportions of the total alpha cell mass. We hypothesize that this functional heterogeneity is a built-in mechanism through which different physiological cues elicit graded glucagon responses from the alpha cells.
Pre-Conception Weight Loss Improves Reproductive, Metabolic and Kidney Health in Obese Mice and Their Offspring
Authors: Rodrigo Natassia , Chen Hui , Pollock Carol , Glastras Sarah
Published: May 2021

Background and Aims: An alarming 40% of women of reproductive age have obesity and during pregnancy obesity adversely impacts metabolic health in mothers and offspring. Maternal complications include diabetes, preeclampsia and chronic kidney disease (CKD). Our previous work showed that offspring have increased risks of obesity, diabetes, and CKD. While pre-pregnancy weight optimisation is advocated, evidence of benefits for mother and offspring are lacking. We aimed to determine if weight loss prior to pregnancy, either with diet modification or liraglutide, improves maternal and offspring metabolic outcomes, and reduces kidney complications in obese mothers and the offspring.

Methods: C57BL/6 female mice were fed a high-fat-diet (HFD) for 8 weeks and compared to lean chow-fed controls. HFD-fed dams were administered liraglutide (0.3mg/kg, s.c., for 4weeks) or switched to chow, to induce pre-conception weight loss. Pregnancy rates were observed after mating. Maternal anthropometry and glucose tolerance were measured before and after intervention, and at late gestation. Pregnant dams were either culled at gestational day 18–20 with blood and kidney harvested, or allowed to deliver their offspring. Offspring anthropometry, and glucose tolerance were assessed at postnatal week 12 after either HFD or chow feeding. Immunohistochemistry (IHC), western blotting and RT-PCR were used to measure kidney metabolic (FAS, SREBP) and inflammatory markers (CD-68,TGF-b). Results: HFD-fed dams had reduced glucose tolerance compared to chow-fed dams (p<0.0001), and higher expression of renal metabolic and inflammatory markers in late gestation (eg FAS <0.05, TGFb <0.05). Intervention with liraglutide or diet lowered body weight, improving glucose tolerance (both p<0.001), and fecundity. Markers of kidney damage, namely albuminuria and fibronectin (by RT-PCR and IHC) were reduced (both p<0.05). Liraglutide treated mice exhibited greater gestational weight gain than mice switched to chow (P<0.001). Markers of inflammation and oxidative stress were significantly lower in obese mice with preconception weight loss via diet compared to liraglutide (eg. MnSOD, PGC1α p<0.05). The offspring of obese mothers with pre-conception weight loss had lower body weight (p<0.001) and improved glucose tolerance (p<0.01). Kidney metabolic and inflammatory markers (MCP-1, FAS, SREBP, CD68) were significantly altered in HFD-fed offspring of obese mothers administered liraglutide pre pregnancy (p<0.05). Conclusions: Preconception weight loss improves fertility, weight and metabolic outcomes in mothers and the offspring, with benefits on reproduction, metabolic health, and chronic kidney disease risk. Therefore, obese women should be targeted for pre-conception weight loss to improve intergenerational metabolic health.
Predictors of Normalization of Fasting Glucose in Patients With Prediabetes Using Remote Continuous Care Emphasizing Low Carbohydrate Intake
Authors: McKenzie Amy , Athinarayanan Shaminie , Adams Rebecca , Hallberg Sarah , Volek Jeff , Phinney Stephen D
Published: May 2021

Background: Prediabetes phenotypes differ based on whether an individual exhibits impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or both. The traditional diabetes prevention approach focused on weight loss via fat/caloric restriction and exercise appears less effective in those with IFG. Given that even transient regression to normal glucose regulation is associated with reduced risk of progression to type 2 diabetes, interventions that elicit normal fasting glucose (NFG) may be beneficial. Here, we explored predictors of normalization of fasting glucose (FG) over one-year treatment with carbohydrate restricted nutrition therapy (Carb-R) delivered via a continuous remote care model.

Methods: Data were obtained from medical records of adults with prediabetes who were treated at least one year at time of analysis. Of 738 patients with an antecedent prediabetes diagnosis, 460 had IFG (100mg/dL to 125mg/dL) at enrollment in the clinic and were included in this analysis. Patients were counseled on Carb-R targeting nutritional ketosis (NK) and reported fasting blood glucose, blood beta-hydroxybutyrate (BHB), and weight via an app facilitating remote monitoring and medical/coaching support. BHB ≥0.5 mM indicated NK. Cox proportional hazard regression was used to model time of first incidence of NFG at 3, 6, 9, and 12 months and to assess if normalization of fasting glucose was associated with baseline factors, weight change, metformin use, and degree or frequency of NK achieved, analyzed separately. Mean±SE is reported.

Results: Patients with IFG were 53.9±0.4 years of age, 64.0% female, HbA1c 5.92±0.02%, and fasting glucose 114.5±0.8 mg/dL at enrollment. During treatment, 199 (43.3%) patients normalized FG at ≥1 time point with mean weight loss of 10.0±0.4 kg (-8.9%) at time of normalization, 192 (41.7%) did not, and 69 (15.0%) were missing glucose data. In an adjusted multivariate model, lower baseline HbA1c (HR 0.60, p=0.03), female sex (HR 1.39, p=0.04), and greater mean BHB value (HR 1.83, p<0.001) or higher proportion of days on which NK was reported (HR 3.23, p<0.001) were associated with reversion to NFG. Age, metformin use, weight change, and baseline fasting glucose, weight, triglycerides, HDL-C, and LDL-C were not associated with reversion to NFG (p>0.05). Conclusions: Greater adherence to Carb-R indicated by greater BHB values and a greater proportion of days in NK were strongly associated with normalization of FG in prediabetes patients with IFG. Weight loss, a common goal for diabetes prevention, was not associated with reversion to NFG. Future studies should assess the effects of Carb-R including NK in other prediabetes phenotypes and on progression to type 2 diabetes.
Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria
Authors: de Souza Cordeiro Leticia M , Devisetty Nagavardhini , McDougal David , Peters Dorien J M , Chhabra Kavaljit H
Published: May 2021

Diabetes increases renal GLUT2 levels and consequently, worsens hyperglycemia by enhancing glucose reabsorption. We recently demonstrated that renal GLUT2 is a primary effector of the central melanocortin system in regulating glucose homeostasis. Therefore, we hypothesized that renal GLUT2 is essential for maintaining systemic glucose homeostasis by regulating glycosuria. To test the hypothesis, we generated kidney-specific inducible Glut2 knockout (KO) mice [Glut2LoxP/LoxP x KspCadCreERT2 (inducible by tamoxifen)]. These mice exhibited 90% reduction in Glut2 expression selectively in the kidneys, without affecting the expressions of other renal glucose transporters, such as Glut1, Sglt1, and Sglt2. To evaluate the physiological contribution of renal GLUT2 in systemic glucose homeostasis, we performed oral glucose tolerance tests (OGTT) in kidney-specific Glut2 KO mice and their control littermates (Ctrl). We observed that the kidney-specific GLUT2 deficient mice exhibited improved glucose tolerance compared to their Ctrls (AUC for OGTT, 41,950 ±2,014 vs. 52,165 ±1,686 mg/dL.min). To measure glycosuria in the kidney-specific Glut2 KO mice, we placed the mice in metabolic cages and collected 24h urine after acclimating the mice in the new cages. Indeed, the GLUT2 deficient mice had ~1,800-fold increase in urine glucose levels (53.5 ±11 vs. 0.03 ±0.005 mg/24h) and exhibited an increased urine volume (2.5 ±0.3 vs. 0.9 ±0.3 mL/24h) and water intake (7.6 ±0.7 vs. 4.9 ±0.7 mL/24h) compared to their Ctrl littermates. The improvement in glucose tolerance in the kidney-specific Glut2 KO mice was independent of the insulin signaling because we did not observe any changes in insulin tolerance tests (ITT) (AUC for ITT, 10,982 ±414 vs. 11,275 ±583 mg/dL.min) and serum insulin levels (1.07 ±0.14 vs. 1.05 ±0.13 ng/mL) between the groups. Importantly, the kidney-specific GLUT2 deficient mice had normal serum creatinine (0.42 ±0.02 vs. 0.41 ±0.03 mg/dL), free fatty acid (0.43 ±0.14 vs. 0.53±0.14 nmol/µL), β-hydroxybutyrate (0.29 ±0.01 vs. 0.27 ±0.02 mM) and glucagon (14 ±4 vs. 10 ±1 pg/mL) levels. Moreover, the kidney-specific Glut2 KO mice had normal glomerular area (4,190 ±119 vs. 4,219 ±186 µm2) as measured by kidney histology and normal glomerular filtration rate (153 ±9 vs. 173 ±10 [µL/min/b.w.]/100) compared with their Ctrl littermates, indicating the absence of any known renal injury. Altogether, we have developed a new mouse model in which we can knockout Glut2 selectively in the kidneys in adult mice. We show that loss-of-function of kidney-specific GLUT2 improves glucose tolerance due to elevated glycosuria without producing any known side effects. In conclusion, blocking kidney-specific GLUT2 has the potential to treat diabetes.